KR20160033146A - Quinine compounds, and optical isomers, preparation method and medical use thereof - Google Patents

Abstract

Disclosed herein are quinone compounds, their pharmaceutically acceptable salts, solvates, precursors and optical isomers thereof. The present invention also discloses that there is a selective blocking action on the M ₁ and M ₃ receptor subtypes of the compounds and that there is no apparent action on the M ₂ receptors and it is known that rhinitis, post-cold rhinitis, chronic tracheitis, airway hyperreactivity, It is effective and effective in treating asthma, chronic obstructive pulmonary disease, coughing, urinary incontinence, urinary frequency, overactive bladder syndrome, bladder spasms, cystitis and gastrointestinal diseases such as irritable bowel syndrome, convulsive colitis and duodenal ulcer and gastric cancer. Long side effects and small side effects.

Description

TECHNICAL FIELD The present invention relates to a quinone compound, an optical isomer thereof, a process for producing the same,

The present invention relates to a quinone compound, an optical isomer thereof, a process for preparing the same, and a composition used for a pharmaceutical purpose including such a compound, and more particularly to a novel M receptor blocker having a selective action on the M receptor subtype. M receptor blockers have a strong action on M ₃ and M ₁ receptor subtypes but not on M ₂ receptor subtypes.

The anticholinergic action of a compound having a quinone structure is disclosed in some patents. For example, the structure of the compounds disclosed in the Chinese invention patent CN200810112248.1 and the invention patent CN200910223255.3 is as follows; R is a methyl group, an ethyl group, a propyl group, an isopropyl group, or a cyclopropyl group; X represents a halogen atom.

French Patent FR2012964 discloses the following structure, wherein R is an H atom, a hydroxy group or an alkyl group of 1-4 carbon atoms; R1 is a phenyl group or thiophene; R2 is cyclohexane, cyclopentane or thiophene.

U.S. Patent No. 5,543,414 discloses the following structure.

International patent application WO01 / 04118 discloses the following structure.

China invention patent CN200810112248.1 Patent of invention patent CN200910223255.3 French patent FR2012964 United States Patent US5654314 International Patent WO01 / 04118

Moon Gwangryeong, Hwajeonggi. Improvement of the synthesis method of 3- (2-phenyl-2-cyclopentylethoxy) quinuclidine hydrochloride. Won, Military Academy, 1988: 470, 402 Oh Bae Kim, Ryu Ryong. Synthesis of anticholinergic drug 2- (1-naphthyl) -2-cyclopentyl-2-hydroxyethoxycyclohydrocarbonamine. China Pharmaceutical Chemical Magazine 1999.6, 9 (2) :, p102-105.

The compounds may be used in the treatment of diseases such as rhinitis, rhinitis after cold, chronic tracheitis, airway hyperresponsiveness, asthma, chronic obstructive pulmonary disease, cough, urinary incontinence, urinary frequency, unstable bladder, bladder spasms, Colonic syndrome, seizure-prone colitis, duodenal ulcer and stomach cancer, the effect is short, the effect is delayed, or the toxic side effect is pronounced.

The compounds of the present invention have overcome the defects of the above compounds. In particular, when treating chronic tracheitis, airway hyperresponsiveness, asthma, and chronic obstructive pulmonary disease, the effect is longer and more effective than the conventional techniques, and toxic side effects And low. The compound of the present invention is suitable for producing an inhalant for treating chronic obstructive pulmonary disease which is highly stable and is administered once a day and is particularly suitable for producing a solution type quantitative inhalation aerosol administered once a day, To the synthesis of such compounds, to the manufacture of pharmaceutical compositions of such compounds and to their pharmaceutical applications.

The compounds of the present invention may also be used in combination with a beta ₂ receptor agonist, a steroid hormone, an antiallergic drug, an antiinflammatory drug, an antiinfective drug, a phopholipase antagonist, etc. to treat the respiratory tract diseases such as rhinitis, Airway hyperresponsiveness, asthma, chronic obstructive pulmonary disease, and the like.

The novel M receptor subtype selective receptor antagonist compounds of the present invention may be represented by the structure of formula (I).

In the formula (I)

n is 1 to 7, preferably 1 to 3, and most preferably 1.

R ₁ is a C ₃ -C ₇ hydrocarbon group which may be unsubstituted or optionally substituted with halogen, alkoxy, alkoxy, hydrocarbon, heterocycle, or aryl groups, but is not limited thereto ; Preferably an unsubstituted cycloalkyl group, and most preferably a cyclopentyl group and a cyclohexyl group.

R ₂ is an aryl group, that is, a phenyl group, a heteroaryl group containing one or a plurality of hetero atoms (the hetero atom may be N, O, S), a naphthyl group or a biphenyl group, And the substituent may be one or more, for example, a halogen, a hydroxy group, a phenyl group, -OR ₆ , -SR ₆ , -NR ₆ R ₇ , -NHCOR ₆ , -CONR ₆ R ₇ , -CN, -NO ₂ , -COOR ₆ , -CF ₃ or C ₁ -C ₄ linear or branched hydrocarbon groups. Preferably an unsubstituted phenyl group, a pyridyl group, a furyl group and a thienyl group. R ₆ and R ₇ may be a hydrogen atom, a C ₁ -C ₄ linear or branched hydrocarbon group, or a cyclic hydrocarbon group formed together.

R ₃ is a hydroxyl group, a halogen, an alkoxy group or an acyloxy group, and the alkoxy group or the acyloxy group may be unsubstituted and may optionally be substituted with a halogen, a hydroxy group, an alkoxy group, a hydrocarbon group, an alkoxy group, a cyclic hydrocarbon group , A heterocycle, an aryl group, but is not limited thereto; Preferably a hydroxy group and a methoxy group, and most preferably a hydroxy group.

R ₄ and R ₅ may or may not be present and when present may be substituents such as, but not limited to, halogen, hydroxy, alkoxyl, hydrocarbon, alkoxyalkyl, heterocycle and aryl.

Y is a C ₁ -C ₇ linear or branched alkyl group or - (CH ₂ -O-CH ₂ ) _m -, m is 1-3, and this group may be optionally substituted and is preferably a halogen, a hydroxy group, an alkoxy An alkoxy group, an alkyl group, an unsaturated hydrocarbon group, a cyclic hydrocarbon group, or a heterocycle; Preferably a methyl group, an ethyl group, a propyl group and - (CH ₂ -O-CH ₂ ) -; Gazing is preferably an ethyl group and a propyl group.

X- is an acid group or a hydroxyl group, a pharmaceutically acceptable acid group, and examples include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, Sulfates, sulfates, bisulfates, sulfites, sulfates, phosphites, and the like; In salts derived from relatively non-toxic organic acids, the organic acids may include, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, Citric acid, tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

Compounds represented by formula (I) may include one or more chiral centers, and single optical isomers thereof or mixtures of various optical isomers are all within the scope of the present invention.

The following compounds can specifically explain the contents of the present invention, but do not limit the scope of the present patent.

1. Synthesis of (2S, 3R) -3- [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

2. Synthesis of (2S, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

3. Synthesis of (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

4. Synthesis of (2R, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

5. Synthesis of (2S, 3R), (2R, 3S) -3- [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] Azabicyclo [2, 2, 2] octane

6. Preparation of (2R, 3R), (2S, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] Azabicyclo [2, 2, 2] octane

7. Preparation of (2S, 3R) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

8. Synthesis of (2S, 3S) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

9. A process for the preparation of (2R, 3R) -3- [(2-cyclohexyl-2- hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

10. Preparation of (2R, 3S) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

11. A process for the preparation of (2R, 3S), (2S, 3R) -3 - [(2-cyclohexyl- Azabicyclo [2, 2, 2] octane

12. A process for the preparation of (2R, 3R), (2S, 3S) -3 - [(2-cyclohexyl- Azabicyclo [2, 2, 2] octane

13. (2S, 3R) -3 - [(2-Cyclobutyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

14. A process for the preparation of (2S, 3S) -3- [(2-cyclobutyl-2- hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

15. A process for preparing (2R, 3S) -3 - [(2-cyclobutyl-2-hydroxy-2- phenyl) ethoxy] 2, 2] octane

16. A process for the preparation of (2R, 3R) -3- [(2-cyclobutyl-2-hydroxy-2- phenyl) ethoxy] 2, 2] octane

17. A process for the preparation of (2R, 3S), (2S, 3R) -3 - [(2-cyclobutyl- Azabicyclo [2, 2, 2] octane

18. A process for the preparation of (2R, 3R), (2S, 3S) -3 - [(2-cyclobutyl- Azabicyclo [2, 2, 2] octane

19. (2S, 3R) -3 - [(2-Cyclopropyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

  20. A process for the preparation of (2R, 3S) -3 - [(2-cyclopropyl-2-hydroxy-2- phenyl) ethoxy] 2, 2] octane

21. (2S, 3S) -3 - [(2-Cyclopropyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

22. A process for the preparation of (2R, 3R) -3 - [(2-cyclopropyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2] octane

23. A process for the preparation of (2R, 3S), (2S, 3R) -3 - [(2- cyclopropyl- Azabicyclo [2, 2, 2] octane

24. (2R, 3R), (2S, 3S) -3 - [(2-Cyclopropyl-2-hydroxy-2- phenyl) ethoxy] Azabicyclo [2, 2, 2] octane

25. (2S, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (2- phenoxyethyl) 2, 2] octane

26. Preparation of (2R, 3R) -3- [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] 2, 2] octane

27. A process for the preparation of (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy ]- 1- phenoxymethyl- octane

28. Preparation of (2R, 3R) -3- [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- phenoxymethoxymethyl-chloro- 2] octane

 29. (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-naphthyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

 30. A process for the preparation of (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- o- chlorophenyl) ethoxy] -1- (3- phenoxypropyl) [2, 2, 2] octane

 31. (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- (3- pyridyl)) ethoxy] -1- (3- phenoxypropyl) Bicyclo [2, 2, 2] octane

  32. A process for the preparation of (2R, 3R) -3 - [(2-cyclopentyl-2- hydroxy- 2- Cyclo [2, 2, 2] octane

33. A process for the preparation of (2R, 3R) -3 - [(2-cyclopentyl-2- hydroxyphenyl) -2- Cyclo [2, 2, 2] octane

The present invention provides the following process route for synthesizing the compound of formula (I).

Step 1: the literature ^(1-2) (1. Door gwangryeong, fivefold gold 3- (2-phenyl-2-cyclopentyl-ethoxy) quinuclidine hydrochloride improved method for the synthesis of Military Medicine Academy wongan, 1988: 470 I Synthesis of 2- (1-naphthyl) -2-cyclopentyl-2-hydroxyethoxycyclohydrocarbylamine compounds, Chinese medicine chemical magazine 1999.6.9 (2): , P102-105.), And 1-R ₁ -1-R ₂ ethylene oxide was prepared, and an aryl-hydrocarbon ketone (some kinds of aryl-hydrocarbon ketones were prepared by reacting a brominated hydrocarbon group and magnesium in THF with Grignard reagent 1-hydrocarbyl group ethylene oxide, i.e., intermediate 1 (represented by the following formula (2)), is prepared by reacting dimethyl sulfoxide and dimethyl sulfide with sodium hydride, )).

Step 2: Preparation of 3 - [(2-R1-2-R2-2-hydroxy) ethoxy] -1-azabicyclo [2,2,2] octane free alkali

Intermediate 1 and quinuclidinol (or R ₄ substituted quinuclidinol) can be obtained intermediate 2 under NaH conditions.

The 3-quinuclidinol derivative sold in the market is dissolved by adding DMSO, sodium hydride is added, the reaction is carried out at 20-60 ° C, the solution is cooled to room temperature, and 1-R ₁ -1-R ₂ -ethylene oxide ) And DMSO is added. When the titration is completed, the mixture is heated to 20-70 ° C by heating in an oil bath for 0.5-12 hours. Ice water is added under an ice bath condition and the internal temperature is maintained at 30 ° C. Extraction with isopropyl ether and washing of the combined ether layer with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The drying agent was filtered off and the solvent was removed by rotary drying to obtain intermediate 2 as a red oil.

Step 3: Purification of 3 - [(2-R ₁ -2-R ₂ -2-hydroxy) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography and related purification

The sample of Intermediate 2 was separated in a silica column, the methanol was added to ammoniated dichloromethane or trichloromethane to form a liquid phase, the purity of the sample was monitored by a TLC plate, and the optical isomer of quinuclidinol (2R, 3S), (2S, 3S) two stereochemistry in the case of quinuclelide S stereoconstitution, intermediate 2 is a mixture containing different optical structures (2R, 3R), (2S, 3S) and (2S, 3S) according to the sequential order of elution, and if the quiniclidolino is in the R configuration, intermediate 2 can be (2S, 3R) and (2R, 3R) according to the sequential order of elution, and if the quinuclidinol racemate is intermediate, then the intermediate 2 (2R, 3S), (2S, 3S), (2R, 3R) (2R, 3S), (2S, 3R) and (2S, 3S), (2R, 3R) can be purified to free alkali according to the order of elution. The free alkali after separation is referred to as intermediate 3.

Step 4 : Preparation of 3-ZY-oxybenzene (Intermediate 4)

Phenol is taken in a three-necked flask, sodium hydroxide is added, and a solution composed of Z-Y-Z (where Z is a halogen atom) and anhydrous alcohol is added and heated under reflux in an oil bath to precipitate a white solid. TLC checking is carried out until the phenol completes the basic phase reaction (TLC conditions: petroleum ether / ethyl ester = 5.0 ml / 1.0 ml). After completion of the reaction, the solid was removed by filtration, and the solvent was removed under reduced pressure of the pump at 50 DEG C or lower to obtain a white solid oil substance. Petroleum ether was added to the filtrate to remove the precipitated solid , And the filtrate is removed under reduced pressure of the pump at 25-40 DEG C to obtain a yellow oil substance. The oil substance was refluxed under reduced pressure to collect a colorless transparent substance.

Step 5: Preparation of compound of formula (I)

Intermediate 2 or Intermediate 3 is taken in a round reaction flask and chloroform is added to dissolve to obtain a yellow transparent solution. Intermediate 4 and acetonitrile are added and reacted with stirring under nitrogen gas protection at room temperature for 10-90 h, (TLC conditions: chloroform / methanol / ammonia = 5.0 ml / 1.5 ml / 2 d) until the reaction is complete. After completion of the reaction, the reaction mixture was rotary-dried under reduced pressure at 25-40 ° C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, and the solid was removed by filtration A white-like solid, i.e., the target compound of formula (I) is obtained.

The compound of the formula (I) may be converted into a hydroxide by removing the halogen through reaction with Ag ₂ O, and may be converted into other acid groups by reacting with other acids. As the salt formed by a pharmaceutically acceptable acid, Examples include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite In salts derived from relatively non-toxic organic acids, the organic acids may include, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, Citric acid, tartaric acid, methanesulfonic acid, glucuronic acid, or galactonic acid, but also salts of amino acids such as arginine.

Any of the medicinal ingredients, including one or more compounds of formula (I), are within the scope of the present patent application, and the medicament can be administered orally, topically, intravenously, Intraarterial administration, intraperitoneal administration, rectal administration, vaginal administration, intranasal administration, inhalation, and the like. The formulation of the present invention can be designed as immediate, immediate, or prolonged. In addition, the drug can be administered via a local rather than systemic route, and by way of representative practice, the composition of the present invention can be composed of a drug suitable for a stray animal, preferably a human.

Compositions comprising one or more compounds of the invention and suitable excipients may be administered in duplicate, or the compositions may be administered sequentially. Suitable sites for drug administration include, but are not limited to, nasal passages, lungs, blood vessels, muscles, bronchi, and stomach. The formulation may be in the form of a liquid, a frozen powder form, a solid or semi-solid form, for example a solution, a suspension, an emulsion, a tablet, a pill, a capsule, a powder, a suppository, Preferably, it is a dosage form capable of administering an accurate dosage unit simply. Examples of suitable excipients include water, saline, lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, Cellulose, syrup, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose and polyacrylic acid, but is not limited thereto. The composition may also contain a lubricant such as talcum, magnesium stearate and mineral oil, a wetting agent, an emulsifier, an antistatic agent, a preservative such as methyl-, ethyl- and propyl-hydroxy-benzoic acid esters, And organic acids and salts, sweeteners and calibrators.

For gastrointestinal external drug administration, the composition may be in the form of sterile injectable solutions and sterile packaged powders. Preferably, injection solutions are prepared at pH 4.5-7.5.

The medicinal compositions of the present invention may also be in the form of tablets, capsules, cachets, emulsions, suspensions, solutions, syrups, elixirs, sprays, pills, troches, powders, Slow-release formulations. Suitable excipients for oral drug administration include medicinal grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate and the like. In the case of tablets for oral administration, a common carrier includes lactose and microcrystalline cellulose, and usually a lubricant such as magnesium stearate is added. In capsules, useful diluents include lactose and dried corn starch, When the drug requires a suspension, the active ingredient may be mixed with the emulsion and the current release agent, and some sweetening, correcting or coloring agents may be added as required.

One or more compounds of the present invention and any one or several pharmaceutically acceptable adjuvants may be dissolved or dispersed in a carrier, for example, a saline solution, aqueous glucose solution, glycerin, alcohol or the like, for example, Solutions, or suspensions used for oral, topical, subcutaneous, topical, subcutaneous, topical, subcutaneous, topical, subcutaneous, topical, subcutaneous, In preparing liquid compositions, liquid suspensions or solutions in the form of solutions may be prepared with aseptic liquids, such as oils, water, alcohols, and combinations thereof, such as: pulmonary inhalation, oral, It is possible to add surfactants, emollients or emulsifiers which are suitable for the medicament, and suspensions may contain oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension formulations may also contain esters of fatty acids, Examples of the suspending agent may include alcohols such as alcohol, isopropanol, cetanol, glycerin and propylene glycol, ethers such as isopropyl alcohol, isopropyl myristate, fatty acid glyceride and acetyl fatty acid glyceride. For example, poly (ethylene glycol), petroleum hydrocarbons such as mineral oil Petroleum jelly, may be used in the water suspension formulation.

Since the composition may be in the form of a pill, tablet or capsule, the composition may contain one or more diluents, such as lactose, sucrose, dicalcium phosphate, etc., disintegrants such as starches or derivatives thereof, lubricants, For example, magnesium stearate and / or an adhesive such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose and derivatives thereof. Pills, tablets or capsules may be prepared by any method known to those skilled in the art.

Or the inventor has discovered that the medicinal composition may be in the form of a suppository for administration of a rectal drug. Such suppositories may be prepared by admixing the drug with a suitable non-irritating excipient that is liquid under room temperature or liquid under rectal temperature and is capable of releasing the drug in rectum. Materials of this type include cocoa butter, beeswax, polyethylene glycols, ground and / or hydrogenated coco glycerides. Compositions suitable for rectal administration may also include rectal enema units, which may include one or more of the compounds of the present invention and a pharmaceutically acceptable solvent (e.g., a 50% aqueous alcohol solution or saline solution) , And such solvent and rectal and / or colon are physiologically compatible. The rectum enema unit preferably comprises an applicator end protected by an inert cover, the end of which is preferably made of polyethylene and is lubricated with a lubricant, for example white vaseline, preferably protected by a one-way valve, Thereby preventing the drug from flowing backward. Rectum enema units are also of sufficient length, preferably 2 inches, to be inserted into the colon through the anus.

The medicinal compositions of the present invention may also be in the form of topical drug administration, particularly when the therapeutic target includes areas or organs that are readily accessible via topical administration, such as, for example, lung, nasal mucosa, have. Local preparations for use in such areas or organs can be readily prepared. For topical drug administration, the composition comprising one or more of the compounds of the present invention may be in the form of a nasal spray, solution inhalant, metered dose inhaler, metered dose inhaler, metered dose inhaler, and the like.

Administration of the drug via inhalation may deliver the dry powder or liquid form of the composition through a spray. Such compositions can be prepared according to the disclosed techniques in the field of drug formulations and can also be prepared using benzyl alcohol or a suitable preservative in saline, absorption promoters, fluorocarbon compounds and / or other conventional solubilizing agents or powders to enhance bioavailability To prepare a solution type composition.

In a solution type quantitative inhalation aerosol containing one or more compounds of Formula (I), the cosolvent includes one or more of anhydrous alcohol, glycerin, diol type, and the diol type thereof includes ethylene But are not limited to, glycol, propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 800. The launching agent includes one of tetrafluoroethane (HFA-134a), heptafluoropropane (HFA-227ea), or a mixture thereof. Such surfactants include oleic acid, oligomeric lactic acid (OLA), dehydrated sorbitol types such as span 20, span 65, span 80, span 85, twin types such as tween 20, tween 80, polyoxyethylene aliphatic alcohol types such as Bri for example, one or more of the following: polyoxyethylene polyoxypropylene copolymers such as Pluronic F-68, polyethylene glycol stearate types such as Solutol HS 15, rigid types such as soy lecithin, . Preferably oleic acid, lecithin, or a mixture of both. In an aerosol, the content by weight percentage of the above formula I compound is 0.005 to 1%, preferably 0.02 to 0.5%. In the suction aerosol, the content of the cosolvent by weight percentage is 5 to 40%, preferably 17.5 to 29.975%. In the inhalation aerosol, the content of the surfactant by weight percentage is 0 to 5%, preferably 0.005 to 2%. In the inhalation aerosol, the content of the launching agent by weight percentage is 54 to 90%, preferably 70 to 80%.

A metered dose inhaler comprising one or more compounds of formula (I), wherein the inert carrier comprises a diluent and a lubricant, wherein the diluent is selected from the group consisting of glucan, arabinose, lactose, mannitol, Mannitol , xylitol, sucrose, fructose, sorbitol, maltose, a mixture of one or more of amino acids and glucose, and the lubricant is magnesium stearate or sodium benzoate.

In a quantitative detergent or a minor spray comprising one or more compounds of formula (I), the inert carrier is selected from the group consisting of benzalkonium chloride, benzalkonium bromide, benzyl alcohol, benzoic acid, acetone chloroform, paraoxybenzoic acid ester type, sorbic acid , Phenol, thymol and a mixture of one or more of petrol.

The present invention also provides for the application of the above drug composition to prevent or treat various acute / chronic airway obstructive diseases such as chronic obstructive pulmonary disease, bronchial asthma and acute / chronic rhinitis and post-cold rhinitis in mammals and humans. And the like.

The combination of a compound of formula (I) with other active ingredients (eg beclomethasone dipropionate, chlortrimethone, napazoline or fenoterol) can result in various acute / chronic airways obstruction Diseases, such as chronic obstructive pulmonary disease, bronchial asthma and various rhinitis.

To obtain a fast and effective therapeutic effect and to avoid toxic side effects during use, the daily recommended dosage of the compound of the present invention is 10-1000 μg, most preferably 40-500 μg.

In addition to the representative formulations described above, other pharmaceutically acceptable excipients, carriers and formulations ordinarily ordinarily skilled in the art are included in the present invention. The specific dose and treatment regimen of any particular patient will be influenced by various factors including the activity of the specific compound employed, the age, weight, general health status, sex, food situation, drug administration time, excretion rate, The compound drug, the judgment of the doctor, and the severity of the specific disease to be treated. The amount of active ingredient is also determined by the specific compound and (if present) the other therapeutic drug in the composition.

Specific implementation method

The following compounds and pure optical isomeric embodiments illustrate the present invention in detail. It should be noted that the present invention is not limited to the following examples. Unless otherwise specified in the examples, all of the components indicate the component proportions by weight.

Example  Preparation of the compound:

[ Example  One] ( 2S, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Step 1: Preparation of 1-phenyl-1-cyclopropyl-phenyl ethylene oxide

1-phenyl-1-cyclophenylethylene oxide is obtained by reacting phenylcyclophenyl ketone commercially available as a raw material according to Document ^{( 1)} .

Step 2 : Preparation of S-3-quinuclidinol 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali

18.72 g (147 mmol) of commercially available S-3-quinuclidinol was taken and 190 ml of DMSO solution was added. 4.56 g (190 mmol) of sodium hydride was added and the mixture was reacted at 20-60 ° C for 0.5 to 12 h, A solution composed of 35.72 g (190 mmol) of 1-phenyl-1-cyclophenylethylene oxide (manufactured by itself) and 45 ml of DMSO was added. After completion of the titration, the mixture was heated to 20-70 ° C in an oil bath, , 120 ml of ice water is added under an ice bath condition, and the inside is titrated while maintaining the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated overnight to remove the drying agent by filtration and the solvent was removed under reduced pressure to obtain a red oil substance 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] 55.7 g of 1-azabicyclo [2, 2, 2] octane free alkali was obtained, and the yield was 97.39%. This is the same as in Example 1 except that 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,3] octane in the (2S, 3S) It is free alkaline.

Step 3 : Purification and purification of 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

Acta Pharm Suec, 1979; 16: 281-283), literature ^(4-5) , ^{(3) (3)} (Bingdahl B, Resul B and Dahlbom R. Facile preparation of the enantiomers of 3-acetoxyquinuclidine and 3-quinuclidinol 4. Synthesis and Separation of Optical Pure Hydroxyether-type Compounds of Goh Gonhwamun, Moon-dongryeong, Chungdang-gu, Kwangju, Korea, 1987. 22 (9): 708-710. Synthesis and Molecular Biology of Cancer R & D and S-type 3-quinuclidinol as raw materials in the Podact Research Center Report, p39-40, 2005, Beijing (Medical Library of Liberation Army: R914, 20050537) Phenyl-2-cyclopentyl oxide or stereoisomer enantiomers of R and S to obtain four optical isomers through column separation. In this document, it is already known that their absolute stereochemistry is determined , And according to the naming principle, a chiral carbon atom on quinuclidine (2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] - 1 -Azabicyclo [2, 2, 2] octane-free alkali. ≪ / RTI >

[Table 1] Compound Absolute Configuration and Nonlinearity Data

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3S ), And (2S, 3S). The alkali of 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [ (2R, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2-phenyl (2S, 3S) -3 - [(2-cyclopentyl-2-hydroxyphenyl) -1,2,3,4-tetrahydroisoquinoline-2-carbonitrile was obtained in a yield of 86.46% Phenyl-ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained in a yield of 77.63%. (2R, 3S) The nonlinearity value [a] _D ^{26 The} actual measured value is +43.95 and the (2S, 3S) nonlinearity value [a] _D ^{26 The} actual measured value is -9.33.

Synthesis and confirmation of other pure optical isomeric bases were carried out using the pure optically isomeric 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [ The target compound can be directly obtained by converting the base to quaternary ammonium. In the specific examples of the synthesis of the specific compounds described below, the production process of various target compounds will be described in detail. The base obtained by using lamecisinuriclinol as a base can be subjected to column separation to obtain a mixture containing four optical isomers, and the final target compound also includes a mixture of four optical isomers. All such pure optical isomers and mixtures of other proportional optical isomers are all within the claims.

Step 4: Preparation of 3-propoxy-benzene bromide

9,107 g (101 mmol) of phenol were placed in a 150 ml three-necked flask, and 4.253 g (106 mmol) of sodium hydroxide was added thereto. A solution composed of 52.17 g (258 mmol) of 1,3-dibromopropane and 30 ml of anhydrous alcohol was added, By heating with an oil bath and proceeding with a refluxing reaction, a white solid precipitates. TLC checking is carried out until the phenol completes the basic phase reaction (TLC conditions: petroleum ether / ethyl acetate = 5.0 ml / 1.0 ml). After completion of the reaction, the solid was removed by filtration, and the solvent was removed under reduced pressure of the pump at 50 DEG C or lower to obtain a white solid oil substance. Petroleum ether was added to the filtrate to remove the precipitated solid , And the filtrate is removed under reduced pressure of the pump at 25-40 DEG C to obtain a yellow oil substance. The oily material was distilled under reduced pressure to collect an effluent of 121-123 DEG C / 8 mmHg to obtain 12.786 g of a colorless transparent oil substance. The yield was 58.9% and the purity by GC inspection was 95.60%.

_{^{1 HNMR (CDCl 3) (ppm}} ): δ7.17-6.77 (m, 5H), δ3.96 (t, 2H), δ3.32 (t, 2H), δ2.21 (m, 2H).

Step 5 : (2R, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.871 g (9.1 mmol) of the (2R, 3S) stereospecific base prepared in Step 2 was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 3-bromopropoxybenzene (51.3 mmol) of acetonitrile and 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until the reaction is complete by TLC (TLC conditions: chloroform / methanol / Nia number = 5.0ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) -bromo-1-azabicyclo [ , 2, 2] octane was obtained. The yield was 80.5%. (2R, 3S) Non-linearity value [a] _D ^{26 The} actual measured value is +53.56.

The compound of Example 1 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through a half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid, and the like. And salts of amino acids such as arginine.

¹ HNMR (D ₂ O) (ppm):? 7.20-6.65 (m, 10H),? 4.15-3.66 (m, 5H),? 2H), 2.01 (m, 1H),? 1.81-1.40 (m, 13H).

[ Example  2]

( 2S, 3S ) -3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3- Phenoxyprop Yl) -bromide-1-azabicyclo [2, 2, 2] octane

1, 2, 3, Step 4 : [ Example  1] 1, 2, 3, Step 4 and  same.

Step 5 : (2S, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.872 g (9.1 mmol) of the (2S, 3S) stereospecific base was placed in a 100 ml eggplant type reaction flask and 18 ml of chloroform was added and dissolved to obtain a yellow transparent solution. 11.332 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2S, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) -bromide- 1 -azabicyclo [ , 2, 2] octane was obtained. The yield was 75.96%. (2S, 3S) Nonlinearity value [a] _D ^{26 The} actual measured value is +31.71.

The compound of Example 2 can be converted to the corresponding salt by reaction with an acid by removing the bromine atom through a half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include, Salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In a salt derived from a non-toxic organic acid, the organic acid may be, for example, acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, paratoluenesulfonic acid, Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O) (ppm):? 7.22-6.66 (m, 10H),? 4.17-3.67 (m, 5H),? 2H), 2.03 (m, 1H),? 1.83-1.41 (m, 13H).

[ Example  3] ( 2S, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 1] Step 1 and same

Step 2 : Alkali preparation of 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane as R-3- quinuclidinol

18.721 g (147 mmol) of commercially available R-3-quinuclidinol was dissolved in 190 ml of a DMSO solution, and 4.558 g (190 mmol) of sodium hydride was added. The mixture was reacted at 20-60 ° C for 0.5-12 h, , And a solution composed of 35.75 g (190 mmol) of 1-phenyl-1-cyclophenylethylene oxide (produced by itself) and 45 ml of DMSO was added. After completion of the titration, the mixture was heated to 20-70 [ The reaction is carried out for a period of time. Under ice bath conditions, 120 ml of ice water is added, and the internal temperature is maintained at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The drying agent was removed by filtration and the solvent was removed by rotary evaporation to give a red oil substance 3- [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] - 1-azabicyclo [2, 2, 2] octane free alkali was obtained. The yield was 95.6%. This can be accomplished by reacting (2R, 3R), (2S, 3R) -3 - [(2-cyclopentyl- to be.

Step 3 : Purification and purification of 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3R ), And (2S, 3R) The two alkali configuration of 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [ (2R, 3R) and (2S, 3R) can be purified according to the sequential order of elution, and (2R, 3R) stereoconstitution 3 - [(2-cyclopentyl- Phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained in a yield of 79.1% and an actual measured value of the nonlinearity value [a] _D ²⁶ was +0.01 2S, 3R) stereochemistry 21.3 g of alkali 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] The yield is 78.37%. Non-linearity value [a] _D ^{26 The} actual measured value is -44.20.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2S, 3R) -3- [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.871 g (9.1 mmol) of the (2S, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.0340 g (51.3 mmol) of 3-bromopropoxybenzene ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2S, 3R) stereochemistry similar to that of 3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2, 2] octane were obtained. The yield was 79.95%. Non-linearity value [a] _D ^{26 The} actual measured value is -58.16.

The compound of Example 3 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O) (ppm): 隆 7.21-6.86 (m, 10H), 隆 4.15-3.66 (m, 5H), 隆 3.43-3.13 (m, 8H) 2H), 2.04 (m, 1H),? 1.79-1.23 (m, 13H).

[ Example  4] ( 2R, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Step 1 : Same as Step 1 of [Example 1]

Steps 2 and 3 : Same as steps 2 and 3 of [Example 3]

Step 4 : Same as step 4 of [Example 1]

Step 5 :

(2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] 2] octane

2.87 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.034 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R) stereochemistry similar to the preparation of 3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2, 2] octane was obtained. The yield was 76.34%. Non-linearity value [a] _D ^{26 The} actual measured value is -31.18.

The compound of Example 4 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through a half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O) (ppm):? 7.22-6.87 (m, 10H),? 4.17-3.65 (m, 5H),? 2H), 2.05 (m, 1H),? 1.80-1.26 (m, 13H).

[ Example  5] (2R, 3S), (2S, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Et Yl] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 1] Step 1 and same

Step 2 : Alkali preparation of racemic quinuclidinol 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2]

18.72 g (147 mmol) of commercially available racemic quinuclidolone was added and 190 ml of DMSO solution was added. 7.59 g (190 mmol) of sodium hydride was added and the mixture was reacted at 20-60 ° C for 0.5 to 12 hours, cooled to room temperature, A solution composed of 35.68 g (190 mmol) of 1-phenyl-1-cyclophenylethylene oxide (produced by itself) and 45 ml of DMSO was added. After completion of the titration, the mixture was heated in an oil bath to 20-70 ° C. for 0.5 to 12 hours, 120 ml ice water is added under an ice bath condition and titrated while keeping the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The drying agent was removed by filtration and the solvent was removed by rotary evaporation to give a red oil substance 3- [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] - 1-azabicyclo [2, 2, 2] octane free alkali was obtained. The yield was 90.92%. (2S, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-aza Bicyclo [2, 2, 2] octane free alkali.

Step 3 : Purification and purification of 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3S (2S, 3R), (2S, 3R), (2S, 3S) (2R, 3R), (2S, 3S) and (2S, 3S) can be purified with two racemic alkali as (2R, 3S) (2R, 3S), (2S, 3R) racemic stereoconstitution. The 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] (2R, 3R), (2S, 3S) stereoselective 3 - [(2-cyclopentyl-cyclohexyl) cyclohexanecarboxylic acid was obtained in the yield of 81.12% 2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2.2.2] Bar for acquiring a 21.29g, yield is 78.33%.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3S), (2S, 3R) stereoconfiguration

2 - [(2-hydroxy-2-phenyl) ethoxy] -1- (3-phenoxypropyl) -bromo-1-azabicyclo [

2.871 g (9.1 mmol) of (2R, 3S), (2S, 3R) stereoisomeric base was placed in a 100 ml eggplant type reaction flask and 18 ml of chloroform was added and dissolved to obtain a yellow transparent solution. 11.35 g (51.3 mmol) of benzene and 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to the TLC test (TLC conditions: chloroform / methanol / Ammonia number = 5.0ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3S), (2S, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -Azabicyclo [2, 2, 2] octane were obtained, and the yield was 71.66%.

The compound of Example 5 can be converted to the corresponding salt by reaction with Ag ₂ O to form a hydroxide by removing the bromine atom through reaction with Ag ₂ O. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.45 m, 2H), 1.96-1.79 (m, 2H), 1.57-1.25 (m, 12H).

[ Example  6] (2R, 3R), (2S, 3S ) Three-dimensional arrangement

3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3- Phenoxypropyl ) -Bromide-1-azabicyclo [2, 2, 2] octane

Step 1 : Same as Step 1 of [Example 1]

Steps 2 and 3 : Same as steps 2 and 3 of [Example 5]

Step 4 : Same as step 4 of [Example 1]

Step 4 : (2R, 3R), (2S, 3S) stereoconfiguration

2 - [(2-hydroxy-2-phenyl) ethoxy] -1- (3-phenoxypropyl) -bromo-1-azabicyclo [

2.87 g (9.1 mmol) of (2R, 3R), (2S, 3S) stereoisomeric base was taken in a 100 ml reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.34 g (51.3 mmol) of benzene and 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to the TLC test (TLC conditions: chloroform / methanol / Ammonia number = 5.0ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R) stereochemistry similar to the preparation of 3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2, 2, 2] octane was obtained. The yield was 74.17%.

From Examples 1 and 3, it was confirmed that four (3) - ((2-cyclopentyl-2-hydroxy-2-phenyl ) Ethoxy] -1-azabicyclo [2, 2, 2] octane free alkali can be obtained. These isomers are mixed in an arbitrary quantity and in an arbitrary proportion, and 3-bromopropoxy Benzene was added to form 4 ammonium and the 3 - [(2-cyclopentyl-2- (2S, 3S) Hydroxy-2-phenyl) ethoxy] -1- (3-phenoxypropyl) -bromo-1-azabicyclo [2,2,2] octane.

The compound of Example 6 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through a half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.18-7.16 (m, 7H), 6.81-6.75 (m, 3H), 3.94-3.45 (m, 5H), 3.25-3.11 m, 2H), 1.97-1.78 (m, 2H), 1.56-1.24 (m, 12H).

[ Example  7] ( 2S, 3R ) -3 - [(2- Cyclohexyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Step 1 : Preparation of 1-phenyl-1-cyclohexylethylene oxide

1-phenyl-1-cyclohexylethylene oxide is obtained by reacting phenylcyclohexylketone commercially available as a raw material according to Document ^{( 1)} .

 Acetonitrile (1880 ml) is taken in a 3 L three-necked flask. When dimethylsulfide and dimethylsulfuric acid are added, the mixture is slightly cooled and stirred for 1.5 hours at room temperature. When NaH (60%) was added to the reaction solution, the mixture was added to the reaction solution several times, and gas was formed (in the case of an external cooler and anhydrous calcium chloride drying vessel), the mixture was added for 30-40 min. After stirring at room temperature for 20 minutes, the mixture was heated in an oil bath to 40-45 ° C., reacted for 90 minutes, cooled at room temperature and allowed to stand overnight . After transferring the reaction mixture to a branch reaction flask, the solvent was removed with a water pump (40-42 ° C, -0.095 MPa), the remaining solid was ice-cooled to 0-5 ° C, and 2630 ml of ice water The reaction mixture was extracted with isopropyl ether (650 ml × 3 times), the ether layer was combined, washed with water until the solution became neutral (pH of the aqueous solution was 7.0) The ether layer is dried over anhydrous sodium sulfate and spent the night. The desiccant is filtered and the water pump is depressurized ((40-42 ° C, -0.095 MPa) to remove the solvent, and then 291.13 grams of 117-127 ° C / 3 mmHg effluent is obtained again with oil pump depressurization.

_{^{1 HNMR (CDCl 3) δ (}} ppm): 7.18-7.10 (m, 5H), 2.91-2.66 (m, 2H), 2.13-1.27 (m, 11H).

Step 2 : Preparation of S-3-quinuclidinol 3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2]

18.72 g (147 mmol) of commercially available S-3-quinuclidinol was taken and 190 ml of DMSO solution was added thereto. 7.59 g (190 mmol) of sodium hydride was added and reacted at 20-60 ° C for 0.5 to 12 hours, , And a solution composed of 38.38 g (190 mmol) of 1-phenyl-1-cyclohexylethylene oxide (manufactured by itself) and 45 ml of DMSO was added and heated to 20-70 ° C with an oil bath , 120 ml of ice water is added under an ice bath condition, and the inside is titrated while maintaining the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The drying agent was removed by filtration and the solvent was removed to give 3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] And 47.102 g of azabicyclo [2, 2, 2] octane free alkali was obtained, and the yield was 97.39%. This can be obtained by reacting (2R, 3S), (2S, 3S) -3 - [(2-cyclohexyl- to be.

Step 3 : Purification and purification of 3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3S ), And (2S, 3S). The alkali of 3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [ (2R, 3S) and (2S, 3S) can be purified in two successive free alkalis according to the sequential order of elution and (2R, 3S) stereoconstitution 3 - [(2-cyclohexyl- Phenyl) ethoxy] -1-azabicyclo [2, 2, 2] octane free alkali was obtained in a yield of 86.12% -Hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2.2.2] octane free alkali was obtained. The yield was 87.6%.

Step 4 : Same as step 4 of [Example 1]

Step 5 :

(2R, 3S) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2] octane

2.994 g (9.1 mmol) of the (2R, 3S) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.034 g (51.3 mmol) of 3-bromopropoxybenzene ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3S) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) -bromide- 1 -azabicyclo [ , 2, 2] octane was obtained. The yield was 81.82%.

The compound of Example 7 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through a half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.16-7.14 (m, 7H), 6.80-6.77 (m, 3H), 3.93-3.42 (m, 5H), 3.24-3.19 m, 2H), 1.89-1.79 (m, 2H), 1.57-1.27 (m, 14H).

[ Example  8]

( 2S, 3S ) -3 - [(2- Cyclohexyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3- Phenoxyprop Yl) -bromide-1-azabicyclo [2, 2, 2] octane

1, 2, 3, Step 4 : [ Example  7] 1, 2, 3, Step 4 and  same.

Step 4 : [ Example 1] Step 4 and same

Step 5 : (2S, 3S) -3 - [(2-Cyclohexyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.993 g (9.1 mmol) of the (2S, 3S) stereospecific base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.035 g (51.3 mmol) of 3-bromopropoxybenzene ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2S, 3S) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) -bromo-1-azabicyclo [ , 2, 2] octane was obtained. The yield was 83.13%.

The compound of Example 8 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through a half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.15-7.14 (m, 7H), 6.82-6.76 (m, 3H), 3.94-3.41 (m, 5H), 3.23-3.18 m, 2H), 1.89-1.79 (m, 2H), 1.58-1.27 (m, 14H).

[ Example  9]

( 2R, 3R ) -3 - [(2- Cyclohexyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3- Phenoxyprop Yl) -bromide-1-azabicyclo [2, 2, 2] octane

Stage 1 : [ Example 7] of 1  Step and same

Step 2 : Alkali preparation of 3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane as R-3- quinuclidinol

18.72 g (147 mmol) of commercially available R-3-quinuclidinol was added, 190 ml of DMSO solution was added, and 7.591 g (190 mmol) of sodium hydride was added. The mixture was reacted at 20-60 ° C for 0.5 to 12 hours, , And a solution composed of 38.38 g (190 mmol) of 1-phenyl-1-cyclohexylethylene oxide (manufactured by itself) and 45 ml of DMSO was added and heated to 20-70 ° C with an oil bath , 120 ml of ice water is added under an ice bath condition, and the inside is titrated while maintaining the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The drying agent was removed by filtration and the solvent was removed to give 3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] 45.89 g of azabicyclo [2, 2, 2] octane free alkali was obtained, and the yield was 96.19%. This is the same as in Example 1 except that 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane in the (2R, 3R) It is free alkaline.

Step 3 : Purification and purification of 3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3R ), And (2S, 3R). The alkali of 3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [ (2R, 3R) -3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) -pyridazinone can be purified by two free alkalis (2R, (2S, 3R) -3 - [(2-cyclohexyl-2-hydroxyphenyl) -1,2,3,4-tetrahydroisoquinoline- 1-azabicyclo [2,2,2] octane free alkali was obtained in a yield of 84.52% Hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained in a yield of 79.26%.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2S, 3R) configuration

(3-phenoxypropyl) -bromo-1-azabicyclo [2.2.2] octane

2.993 g (9.1 mmol) of the (2S, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.0340 g (51.3 mmol) of 3-bromopropoxybenzene ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was distilled off under reduced pressure at 25-40 ° C to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid. The solid was filtered to obtain a white solid 2, 3R) -3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] -1 - (3- phenoxypropyl) 2] octane were obtained. The yield was 83.03%.

The compound of Example 9 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through the half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.16-7.14 (m, 7H), 6.80-6.77 (m, 3H), 3.93-3.42 (m, 5H), 3.24-3.19 m, 2H), 1.89-1.79 (m, 2H), 1.57-1.27 (m, 14H).

[ Example 10] (2R, 3R ) -3 - [(2- Cyclohexyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 7] of 1  Step and same

2, Step 3 : [ Example 9]  2, Step 3 and same

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3R) -3 - [(2-Cyclohexyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) -bromo-1-azabicyclo [ , 2, 2] octane

2.995 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.034 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was distilled off under reduced pressure at 25-40 ° C to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid. The solid was filtered to obtain a white solid 2 - [(3-phenoxypropyl) -bromo-l-azabicyclo [2.2.2] octan-2- 2] octane were obtained, and the yield was 84.95%.

The compound of Example 10 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.16-7.14 (m, 7H), 6.81-6.77 (m, 3H), 3.93-3.42 (m, 5H), 3.24-3.19 m, 2H), 1.89-1.78 (m, 2H), 1.57-1.27 (m, 14H).

[Example 11] Synthesis of (2R, 3S), (2S, 3R ) Three-dimensional Batch 3 -[(2- Cyclohexyl 2-phenyl) ethoxy] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 7] Step 1 and same

Step 2 : Alkali preparation of racemic quinuclidinol 3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2]

18.72 g (147 mmol) of commercially available racemic quinuclidolone was added and 190 ml of DMSO solution was added. 7.59 g (190 mmol) of sodium hydride was added and the mixture was reacted at 20-60 ° C for 0.5 to 12 hours, cooled to room temperature, A solution composed of 38.42 g (190 mmol) of 1-phenyl-1-cyclohexylethylene oxide (manufactured by itself) and 45 ml of DMSO was added. After completion of the titration, the mixture was heated to 20-70 ° C for 0.5-12 hours, 120 ml ice water is added under an ice bath condition and titrated while keeping the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The drying agent was removed by filtration and the solvent was removed under reduced pressure to obtain a red oil substance 3- [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] 43.58 g of 1-azabicyclo [2,2,2] octane free alkali was obtained, and the yield was 90.12%. (3R, 3R), (2S, 3R), (2S, 3R) - azabicyclo [2, 2, 2] octane glass alkali.

Step 3 : Purification and purification of 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3S (2S, 3R), (2S, 3R), (2S, 3S) (2R, 3R), (2S, 3S) and (2S, 3S) can be purified with two racemic alkali as (2R, 3S) (2R, 3S), (2S, 3R) racemic stereoconstitution 3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] (2R, 3R), (2S, 3S) stereoconstitution 3 - [(2-cyclopentyl-2- Hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane glass alkali Bar to benefit, the yield is 79.35%.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3S), (2S, 3R) stereoconjugate 3 - [(2-Cyclohexyl-2-hydroxy-2- phenyl) ethoxy] 1-Azabicyclo [2,2,2] octane

2.993 g (9.1 mmol) of (2R, 3S) and (2S, 3R) stereoisomeric base were taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.34 g (51.3 mmol) of benzene and 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to the TLC test (TLC conditions: chloroform / methanol / Ammonia number = 5.0ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3S), (2S, 3R) stereochemistry 3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] 4.026 g of 1-azabicyclo [2, 2, 2] octane was obtained, and the yield was 81.36%.

The compound of Example 11 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through the half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.78 (m, 3H), 3.93-3.42 (m, 5H), 3.24-3.19 m, 2H), 1.88-1.79 (m, 2H), 1.58-1.26 (m, 14H).

[ Example  12] (2R, 3R), (2S, 3S ) -3 - [(2- Cyclohexyl -2-hydroxy-2-phenyl) Et Yl] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 7] of 1  Step and same

2, Step 3 : [ Example 11]  2, Step 3 and same

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3R), (2S, 3S) stereoconstitution 3 - [(2-Cyclohexyl-2-hydroxy-2- phenyl) ethoxy] 1-Azabicyclo [2,2,2] octane

2.994 g (9.1 mmol) of the (2R, 3R) stereoisomeric base of (2R, 3R) and (2S, 3S) was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.34 g (51.3 mmol) of benzene and 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to the TLC test (TLC conditions: chloroform / methanol / Ammonia number = 5.0ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was distilled off under reduced pressure at 25-40 ° C to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid. The solid was filtered to obtain a white solid 2R, 3R), (2S, 3S) -3 - [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] -1 - (3- phenoxypropyl) Cyclohexyl [2,2,2] octane was obtained, and the yield was 83.36%.

(2S, 3S), (2S, 3R), (2S, 3S) four stereoisomeric forms of 3 - [(2-cyclohexyl- ) Ethoxy] -1-azabicyclo [2, 2, 2] octane free alkali can be obtained. These isomers are mixed in an optional amount and in any proportion, and 4ammonium 3- Addition of brominated propoxybenzene gave 3 - [(2-cyclohexyl-2-hydroxyphenyl) -propan-2-ol with different proportions of (2R, 3S), (2R, 3R), (2S, Hydroxy-2-phenyl) ethoxy] -1- (3-phenoxypropyl) -bromo-1-azabicyclo [2,2,2] octane.

The compound of Example 12 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.16-7.14 (m, 7H), 6.80-6.77 (m, 3H), 3.93-3.42 (m, 5H), 3.24-3.19 m, 2H), 1.89-1.79 (m, 2H), 1.57-1.27 (m, 14H).

[ Example  13] ( 2R, 3S ) -3 - [(2- Cyclobutyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Step 1 : Preparation of 1-phenyl-1-cyclobutylethylene oxide

1-phenyl-1-cyclobutylethylene oxide is obtained by reacting phenylcyclobutylketone commercially available as a raw material according to literature ^{( 1)} .

Acetonitrile (1880 ml) is taken in a 3 L three-necked flask. When dimethylsulfide and dimethylsulfuric acid are added, the mixture is slightly cooled and stirred for 1.5 hours at room temperature. When NaH (60%) is taken with stirring, it is added to the reaction solution several times to generate gaseous matter (in the case of an external cooler and anhydrous calcium chloride drying vessel), the mixture is added in the range of 30-40 min, And 315.6 grams of phenylcyclobutyl ketone. After stirring for about 20 minutes at room temperature, the mixture is heated to 40-45 ° C in an oil bath, reacted for 90 minutes, allowed to cool at room temperature, and then allowed to stand overnight. After transferring the reaction mixture to a branch reaction flask, the solvent was removed with a water pump (40-42 ° C, -0.095 MPa), the remaining solid was ice-cooled to 0-5 ° C, and 2630 ml of ice water The reaction mixture was extracted with isopropyl ether (650 ml × 3 times), the ether layer was combined, washed with water until the solution became neutral (pH of the aqueous solution was 7.0) The ether layer is dried over anhydrous sodium sulfate and spent the night. The desiccant was filtered and the solvent was removed under reduced pressure (40-42 占 폚, -0.095 MPa), then 282.7 grams of 113-126 占 폚 / 3 mmHg effluent was obtained again with oil pump vacuum, yielding 82.37% .

_{^{1 HNMR (CDCl 3) δ (}} ppm): 7.19 (m, 5H), 2.92-2.65 (m, 2H), 2.61 (m, 1H), 2.03-1.77 (m, 6H).

Step 2 : Preparation of S-3-quinuclidinol 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali

18.72 g (147 mmol) of commercially available S-3-quinuclidinol was taken and 190 ml of DMSO solution was added thereto. 7.59 g (190 mmol) of sodium hydride was added and reacted at 20-60 ° C for 0.5 to 12 hours, , A solution composed of 33.054 g (190 mmol) of 1-phenyl-1-cyclobutyl ethylene oxide (manufactured by the company) and 45 ml of DMSO was added. After completion of the titration, the mixture was heated to 20-70 ° C in an oil bath, , 120 ml of ice water is added under an ice bath condition, and the inside is titrated while maintaining the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove the drying agent. The solvent was removed to obtain a red oil substance 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] 43.473 g of 1-azabicyclo [2,2,2] octane free alkali was obtained, and the yield was 98.25%. This is the same as in Example 1 except that 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,3] octane in the (2S, It is free alkaline.

Step 3 : Purification and purification of 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3S ), And (2S, 3S). The three-dimensional arrangement of 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [ (2R, 3S) -3 - [(2-Cyclobutyl-2-hydroxy-2-phenyl) -pyridine can be purified by two free alkalis, (2S, 3S) -3 - [(2-cyclobutyl-2-hydroxyphenyl) ethoxy] -1-azabicyclo [ Phenyl-ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained in a yield of 79.62%.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3S) -3 - [(2-Cyclobutyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) -bromo-1-azabicyclo [ , 2, 2] octane

2.7.39 g (9.1 mmol) of the (2R, 3S) stereospecific base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.034 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was distilled under a reduced pressure of water at 25-40 캜 to obtain a yellow oily substance. Ethyl ether was added to precipitate a large amount of solid. The solid was filtered to obtain a white solid (2R, 3R) stereoconfiguration 3 - [(2-Cyclobutyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2] octane was obtained. The yield was 81.52%.

The compound of Example 13 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through a half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 5H), 3.49-3.19 , ≪ / RTI > 2H), 2.0-1.79 (m, 11H).

[ Example  14] ( 2S, 3S ) -3 - [(2- Cyclobutyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

1, 2, Step 3 : [ Example  13] 1, 2, Step 3 and  same.

Step 4 : [ Example 1] Step 4 and same

Step 5 : (2S, 3S) -3 - [(2-Cyclobutyl-2- hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) -bromo-1-azabicyclo [ , 2, 2] octane

2.7.39 g (9.1 mmol) of the (2S, 3S) stereospecific base was taken in a 100 ml reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.034 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was distilled off under reduced pressure at 25-40 ° C to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid. The solid was filtered to obtain a white solid 2 - [(3-phenoxypropyl) -bromo-1-azabicyclo [2.2.2] 2] octane were obtained. The yield was 79.34%.

The compound of Example 14 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through the half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 5H), 3.49-3.19 , ≪ / RTI > 2H), 2.0-1.79 (m, 11H).

[ Example  15] ( 2S, 3R ) -3 - [(2- Cyclobutyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 13] of 1  Step and same

Step 2 : Alkali preparation of 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane as R-3- quinuclidinol

18.721 g (147 mmol) of commercially available R-3-quinuclidolone was added and 190 ml of DMSO solution was added. 7.591 g (190 mmol) of sodium hydride was added and reacted at 20-60 ° C for 0.5-12 h, , A solution composed of 33.054 g (190 mmol) of 1-phenyl-1-cyclobutyl ethylene oxide (manufactured by the company) and 45 ml of DMSO was added. After completion of the titration, the mixture was heated to 20-70 ° C in an oil bath, , 120 ml of ice water is added under an ice bath condition, and the inside is titrated while maintaining the internal temperature at 30 占 폚. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove the drying agent. The solvent was removed to obtain a red oil substance 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] 4.591 g of 1-azabicyclo [2,2,2] octane free alkali was obtained, and the yield was 97.77%. This is the same as in Example 1 except that 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,3] octane in the (2R, 3R) It is free alkaline.

Step 3 : Purification and purification of 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3R ), And (2S, 3R) The two alkali configuration of 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [ (2R, 3R) - (2-cyclobutyl-2-hydroxy-2-phenyl) -pyridine can be purified by two free alkalis according to the following sequence of elution: (2R, (2S, 3R) -3 - [(2-cyclobutyl-2-hydroxyphenyl) ethoxy] -1-azabicyclo [ Hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2.2.2] octane free alkali was obtained. The yield was 79.59%.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2S, 3R) -3- [(2-Cyclobutyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.7.39 g (9.1 mmol) of the (2S, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.0340 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was distilled off under reduced pressure at 25-40 ° C to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid. The solid was filtered to obtain a white solid 2 - [(3-phenoxypropyl) -bromo-l-azabicyclo [2.2.2] hept- 2] octane was obtained. The yield was 80.72%.

The compound of Example 15 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 5H), 3.49-3.19 , ≪ / RTI > 2H), 2.0-1.79 (m, 11H).

[ Example  16] ( 2R, 3R ) -3 - [(2- Cyclobutyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 13] of 1  Step and same

2, Step 3 : [ Example 15] of  2, Step 3 and same

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3R) -3- [(2-Cyclobutyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.7.39 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.034 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was distilled under a reduced pressure of water at 25-40 캜 to obtain a yellow oily substance. Ethyl ether was added to precipitate a large amount of solid. The solid was filtered to obtain a white solid (2R, 3R) stereoconfiguration 3 - [(2-Cyclobutyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2] octane was obtained. The yield was 81.02%.

The compound of Example 16 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.14 (m, 7H), 6.81-6.77 (m, 3H), 3.94-3.68m, 5H), 3.49-3.19 , ≪ / RTI > 2H), 2.0-1.77 (m, 11H).

[Example 17] Synthesis of (2R, 3S), (2S, 3R ) -3 - [(2- Cyclobutyl -2-hydroxy-2-phenyl) Et Yl] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 13] of 1  Step and same

Step 2 : Alkali preparation of racemic quinuclidinol 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [

18.72 g (147 mmol) of commercially available racemic quinuclidolone was added and 190 ml of DMSO solution was added. 7.59 g (190 mmol) of sodium hydride was added and the mixture was reacted at 20-60 ° C for 0.5 to 12 hours, cooled to room temperature, A solution composed of 33.06 g (190 mmol) of 1-phenyl-1-cyclobutyl ethylene oxide (manufactured by itself) and 45 ml of DMSO was added. After completion of the titration, the mixture was heated in an oil bath to 20-70 ° C. for 0.5 to 12 hours, 120 ml ice water is added under an ice bath condition and titrated while keeping the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove the drying agent. The solvent was removed to obtain a red oil substance 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] 42.16 g of 1-azabicyclo [2, 2, 2] octane free alkali was obtained, and the yield was 95.28%. (2S, 3S) -3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-aza Bicyclo [2, 2, 2] octane free alkali.

Step 3 : Purification and purification of 3 - [(2-cyclobutyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3S (2S, 3R), (2S, 3R), (2S, 3S) (2R, 3R), (2S, 3S) and (2S, 3S) can be purified with two racemic alkali as (2R, 3S) (2R, 3S), (2S, 3R) racemic stereoconstitution 3 - [(2-cyclobutyl-2-hydroxy-2- phenyl) ethoxy] (2R, 3R), (2S, 3S) stereoconstitution 3 - [(2-cyclobutyl-2- Hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2.2.2] octane free alkali Bar to benefit, the yield is 79.36%.

Step 4 : Same as step 4 of [Example 1]

Step 5: (2R, 3S), (2S, 3R) -3 - [(2-Cyclobutyl- 2- hydroxy- 2- phenyl) ethoxy] -1- (3- phenoxypropyl) - azabicyclo [2, 2, 2] octane

2.739 g (9.1 mmol) of the (2R, 3S) and (2S, 3R) stereoisomeric base were taken in a 100 ml reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.3342 g (51.3 mmol) of benzene and 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to TLC test (TLC conditions: chloroform / methanol / Ammonia number = 5.0ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was distilled off under reduced pressure at 25-40 ° C to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid. The solid was filtered to obtain a white solid 2R, 3S), (2S, 3R) stereoconstitution 3 - [(2-cyclobutyl-2-hydroxy-2- phenyl) ethoxy] Cyclohexyl [2,2,2] octane was obtained, and the yield was 83.38%.

The compound of Example 17 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through a half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 5H), 3.49-3.19 , ≪ / RTI > 2H), 2.0-1.79 (m, 11H).

[ Example  18] (2R, 3R), (2S, 3S ) -3 - [(2- Cyclobutyl -2-hydroxy-2-phenyl) Et Yl] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

1, 2, Step 3 : [ Example  17] 1, 2, Step 3 and  same.

Step 4 : Same as step 4 of [Example 1]

Step 5: (2R, 3R), (2S, 3S) -3 - [(2-Cyclobutyl- 2- hydroxy- 2- phenyl) ethoxy] -1- (3- phenoxypropyl) - azabicyclo [2, 2, 2] octane

2.7.39 g (9.1 mmol) of the (2S, 3S) stereoisomeric base of (2R, 3R) and (2S, 3S) was taken in a 100 ml eggplant type reaction flask, and 18 ml of chloroform was added thereto to dissolve to obtain a yellow transparent solution. 11.34 g (51.3 mmol) of benzene and 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to the TLC test (TLC conditions: chloroform / methanol / Ammonia number = 5.0ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R), (2S, 3S) stereoselective preparation of 3 - [(2-cyclobutyl- 2- hydroxy- 2- phenyl) ethoxy] -1- (3- phenoxypropyl) 3.918 g of 1-azabicyclo [2, 2, 2] octane was obtained, and the yield was 83.42%.

(2R, 3R), (2S, 3R) and (2S, 3S) four stereoisomeric forms of 3 - [(2-cyclobutyl- ) Ethoxy] -1-azabicyclo [2, 2, 2] octane free alkali can be obtained. These isomers are mixed in an optional amount and in any proportion, and 4ammonium 3- Addition of brominated propoxybenzene gives 3 - [(2-cyclobutyl-2-hydroxymethyl) -2-methylpropyl] -benzene which contains different proportions of (2R, 3S), (2R, 3R), (2S, Hydroxy-2-phenyl) ethoxy] -1- (3-phenoxypropyl) -bromo-1-azabicyclo [2,2,2] octane.

The compound of Example 18 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through the half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 5H), 3.49-3.19 , ≪ / RTI > 2H), 2.0-1.79 (m, 11H).

[ Example  19] ( 2R, 3S ) -3 - [(2- Cyclopropyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Step 1 : Preparation of 1-phenyl-1-cyclopropylethylene oxide

1-phenyl-1-cyclopropylethylene oxide is obtained by reacting phenylcyclopropylketone commercially available as a raw material according to literature ^{( 1)} .

Acetonitrile (1880 ml) is taken in a 3 L three-necked flask. When dimethylsulfide and dimethylsulfuric acid are added, the mixture is slightly cooled and stirred for 1.5 hours at room temperature. When NaH (60%) is taken with stirring, it is added to the reaction solution several times to generate gaseous matter (in the case of an external cooler and anhydrous calcium chloride drying vessel), the mixture is added in the range of 30-40 min, And 300.5 grams of phenylcyclopropyl ketone. After stirring for about 20 minutes at room temperature, the mixture was heated to 40-45 ° C in an oil bath and reacted for 90 minutes. The mixture was allowed to cool at room temperature overnight. After transferring the reaction mixture to a branch reaction flask, the solvent was removed with a water pump (40-42 ° C, -0.095 MPa), the remaining solid was ice-cooled to 0-5 ° C, and 2630 ml of ice water The reaction mixture was extracted with isopropyl ether (650 ml × 3 times), the ether layer was combined, washed with water until the solution became neutral (pH of the aqueous solution was 7.0) The ether layer is dried over anhydrous sodium sulfate and spent the night. The desiccant was filtered, and the solvent was removed under reduced pressure (40-42 DEG C, -0.095 MPa), and then 275.8 grams of 111-124 DEG C / 3 mmHg effluent was recovered by oil pump decompression, yielding 83.75% .

_{^{1 HNMR (CDCl 3) δ (}} ppm): 7.19 (m, 5H), 2.91-2.66 (m, 2H), 0.91 (m, 1H), 0.31-0.07 (m, 4H).

Step 2 : Preparation of S-3-quinuclidinol 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [

18.72 g (147 mmol) of commercially available S-3-quinuclidinol was taken and 190 ml of DMSO solution was added thereto. 7.59 g (190 mmol) of sodium hydride was added and reacted at 20-60 ° C for 0.5 to 12 hours, , A solution composed of 30.35 g (190 mmol) of 1-phenyl-1-cyclopropylethylene oxide (manufactured by itself) and 45 ml of DMSO was added and heated to 20-70 ° C in an oil bath , 120 ml of ice water is added under an ice bath condition, and the inside is titrated while maintaining the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated overnight to remove the drying agent by filtration and the solvent was removed under reduced pressure to give 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] 41.40 g of 1-azabicyclo [2, 2, 2] octane free alkali was obtained, and the yield was 98.13%. This can be obtained by reacting 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,3] octane in the (2S, It is free alkaline.

Step 3 : Purification and purification of 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3S ), And (2S, 3S). The alkali of 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [ (2R, 3S) -3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) -pyridine can be purified by two free alkalis according to the following sequence of elution: (2R, (2S, 3S) -3 - [(2-cyclobutyl-2-hydroxyphenyl) -1,2,3,4-tetrahydroisoquinolin- Phenyl-ethoxy] -1-azabicyclo [2, 2, 2] octane free alkali was obtained in a yield of 79.68%.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3S) -3 - [(2-Cyclopropyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.6.1 g (9.1 mmol) of the (2R, 3S) stereoselective base was placed in a 100 ml eggplant type reaction flask, and 18 ml of chloroform was added to dissolve to obtain a yellow transparent solution. 11.034 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was distilled off under reduced pressure at 25-40 ° C to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid. The solid was filtered to obtain a white solid 2 - [(3-phenoxypropyl) -bromo-l-azabicyclo [2.2.2] hept- 2] octane were obtained, and the yield was 81.55%.

The compound of Example 19 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through the half of the Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 4H), 3.49-3.19 , 2H), 1.82-1.57 (m, 5H), 0.67-0.06 (m, 5H).

[ Example  20] ( 2S, 3S ) -3 - [(2- Cyclopropyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

1, 2, Step 3 : [ Example  19] 1, 2, Step 3 and  same.

Step 4 : [ Example 1] Step 4 and same

Step 5 : (2S, 3S) -3 - [(2-Cyclopropyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.6.1 g (9.1 mmol) of the (2S, 3S) stereoselective base was placed in a 100 ml eggplant type reaction flask, and 18 ml of chloroform was added to dissolve to obtain a yellow transparent solution. 11.034 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2S, 3S) stereochemistry similar to that of 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] 2, 2, 2] octane was obtained. The yield was 82.66%.

The compound of Example 20 reacts with Ag ₂ O to form a hydroxide by eliminating the bromine atom and can be converted to the corresponding salt by reaction with other acid. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.81-6.77 (m, 3H), 3.94-3.68m, 4H), 3.49-3.19 , 2H), 1.82-1.57 (m, 5H), 0.66-0.06 (m, 5H).

[ Example  21] ( 2S, 3R ) -3 - [(2- Cyclopropyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 19] of 1  Step and same

Step 2 : Alkali preparation of 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2.2.2] octane as R-3- quinuclidinol

18.721 g (147 mmol) of commercially available R-3-quinuclidolone was added and 190 ml of DMSO solution was added. 7.591 g (190 mmol) of sodium hydride was added and reacted at 20-60 ° C for 0.5-12 h, , A solution composed of 30.36 g (190 mmol) of 1-phenyl-1-cyclopropylethylene oxide (manufactured by itself) and 45 ml of DMSO was added and heated to 20-70 ° C in an oil bath , 120 ml of ice water is added under an ice bath condition, and the inside is titrated while maintaining the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated overnight to remove the drying agent by filtration and the solvent was removed by rotary evaporation to give a red oil substance 3 - [(2-cyclopropyl-2-hydroxy- ] -1-azabicyclo [2, 2, 2] octane free alkali was obtained in a yield of 97.15%. This is the same as that of 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,3] octane in the (2R, 3R) It is free alkaline.

Step 3 : Purification and purification of 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3R ), And (2S, 3R). The alkali of 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [ (2R, 3R) -3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) -pyridine can be purified by two free alkalis according to the following sequence of elution: (2R, (2S, 3R) stereoisomeric 3 - [(2-cyclobutyl-2-methylphenyl) Hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained, yielding 79.34%.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2S, 3R) -3 - [(2-Cyclopropyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.6.1 g (9.1 mmol) of the (2S, 3R) stereoconstituent base was placed in a 100 ml eggplant type reaction flask, and 18 ml of chloroform was added to dissolve to obtain a yellow transparent solution. 11.0340 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, -1 - (- 3-phenoxypropyl) -bromo-l-azabicyclo [6.2.1.0 < 2,6 > 2, 2, 2] octane was obtained. The yield was 78.78%.

The compound of Example 21 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 4H), 3.49-3.19 , 2H), 1.82-1.57 (m, 5H), 0.67-0.06 (m, 5H).

[ Example  22] ( 2R, 3R ) -3 - [(2- Cyclopropyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 19] Step 1 and same

2, Step 3 : [ Example 21]  2, Step 3 and same

Step 4 : Same as step 4 of [Example 1]

Step 4 : (2R, 3R) -3 - [(2-Cyclopropyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane

2.612 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.034 g (51.3 mmol ) And 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to TLC test (TLC conditions: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 캜 to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, - (3-phenoxypropyl) -bromo-l-azabicyclo [2.2. ≪ RTI ID = 0.0 > 2, 2, 2] octane was obtained. The yield was 83.07%.

The compound of Example 22 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through the half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 4H), 3.49-3.19 , 2H), 1.82-1.57 (m, 5H), 0.67-0.06 (m, 5H).

[Example 23] (2R, 3S), (2S, 3R ) -3 - [(2- Cyclopropyl -2-hydroxy-2-phenyl) Et Yl] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 19] of 1  Step and same

Step 2 : Alkali preparation of racemic quinuclidinol 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane

18.72 g (147 mmol) of commercially available racemic quinuclidolone was added and 190 ml of DMSO solution was added. 7.59 g (190 mmol) of sodium hydride was added and the mixture was reacted at 20-60 ° C for 0.5 to 12 hours, cooled to room temperature, A solution composed of 30.4 g (190 mmol) of 1-phenyl-1-cyclopropylethylene oxide (manufactured by itself) and 45 ml of DMSO was added. After completion of the titration, the mixture was heated to 20-70 ° C for 0.5-12 hours, 120 ml ice water is added under an ice bath condition and titrated while keeping the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated overnight to remove the drying agent by filtration and the solvent was removed by rotary evaporation to give a red oil substance 3 - [(2-cyclopropyl-2-hydroxy- ] -1-azabicyclo [2, 2, 2] octane free alkali was obtained in a yield of 99.6%. (2S, 3R), (2S, 3R), (2S, 3S) stereoisomers of 3 - [(2-cyclopropyl- - azabicyclo [2, 2, 2] octane glass alkali.

Step 3 : Purification and purification of 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography

The sample in the first step was separated in a silica column, added to ammonia dichloromethane or trichloromethane to form a liquid phase, and the purity of the sample was monitored with a TLC plate. The sample (2R, 3S ), (2S, 3R), (2S, 3R), (2S, 3S) (2R, 3R), (2S, 3S) and (2S, 3S) can be purified with two racemic alkali as (2R, 3S) (2R, 3S), (2S, 3R) racemic stereoregular 3 - [(2-cyclopropyl-2-hydroxy-2-phenyl) ethoxy] (2R, 3R), (2S, 3S) stereoselectivity was obtained in the same manner as in Example 1, except that 17.06 g of [2, 2, 2] octane free alkali was obtained in a yield of 81.22% Hydroxy-2-phenyl) ethoxy] -1-azabicyclo [2,2,2] octane glass alkali 16 . The yield was 79.13%.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3S), (2S, 3R) stereoconstitution A solution of 3 - [(2- cyclopropyl-2- hydroxy-2- phenyl) ethoxy] 1-Azabicyclo [2,2,2] octane

2.6.1 g (9.1 mmol) of (2R, 3S), (2S, 3R) stereoisomeric base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.3342 g (51.3 mmol) of benzene and 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to TLC test (TLC conditions: chloroform / methanol / Ammonia number = 5.0ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3S), (2S, 3R) stereochemistry 3 - [(2-Cyclopropyl-2- hydroxy-2- phenyl) ethoxy] 3.76 g of 1-azabicyclo [2, 2, 2] octane was obtained, and the yield was 82.31%.

The compound of Example 23 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through the half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 4H), 3.49-3.19 , 2H), 1.82-1.57 (m, 5H), 0.67-0.06 (m, 5H).

[ Example  24] (2R, 3R), (2S, 3S ) Three-dimensional Batch 3 -[(2- Cyclopropyl 2-phenyl) ethoxy] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 19] of 1  Step and same

2, Step 3 : [ Example 23]  2, Step 3 and same

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3R), (2S, 3S) stereoconstitution 3 - [(2- cyclopropyl-2- hydroxy-2- phenyl) ethoxy] 1-Azabicyclo [2,2,2] octane

2.621 g (9.1 mmol) of (2R, 3R), (2S, 3S) stereoisomeric base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.34 g (51.3 mmol) of benzene and 50 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to the TLC test (TLC conditions: chloroform / methanol / Ammonia number = 5.0ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R), (2S, 3S) stereochemistry 3 - [(2-Cyclopropyl-2-hydroxy-2- phenyl) ethoxy] 3.54 g of 1-azabicyclo [2, 2, 2] octane was obtained, and the yield was 77.49%.

(2R, 3R), (2S, 3R), (2S, 3S) four stereoregular forms of 3 - [(2-cyclopropyl- ) Ethoxy] -1-azabicyclo [2, 2, 2] octane free alkali can be obtained. These isomers are mixed in an optional amount and in any proportion, and 4ammonium 3- Addition of bromopropoxybenzene affords 3 - [(2-cyclopropyl-2-hydroxyphenyl) -2,3-dihydroxybenzene, which contains different proportions of the (2R, 3S), (2R, 3R), (2S, Hydroxy-2-phenyl) ethoxy] -1- (3-phenoxypropyl) -bromo-1-azabicyclo [2,2,2] octane.

The compound of Example 24 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O)? (Ppm): 7.19-7.15 (m, 7H), 6.82-6.77 (m, 3H), 3.94-3.68m, 4H), 3.49-3.19 , 2H), 1.82-1.57 (m, 5H), 0.67-0.06 (m, 5H).

[ Example  25] ( 2S, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (2-phenoxyethyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 1] Step 1 and same

2, Step 3 : [ Example 3]  2, Step 3 and same

Step 4 : Preparation of 2-bromoethoxybenzene

9.5 g (101 mmol) of phenol were placed in a 150 ml three-necked flask, and 4.25 g (106 mmol) of sodium hydroxide was added thereto. A solution composed of 47.11 g (250 mmol) of 1,2-dibromoethane and 30 ml of anhydrous alcohol was added, By heating with an oil bath and proceeding with a refluxing reaction, a white solid precipitates. TLC checking is carried out until the phenol completes the basic phase reaction (TLC conditions: petroleum ether / ethyl acetate = 5.0 ml / 1.0 ml). After completion of the reaction, the solid was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure of water pump at 50 DEG C or lower to obtain a white solid oil substance. Petroleum ether was added to the residue to precipitate by filtration And the filtrate is rotary evaporated under reduced pressure of water pump at 25-40 ° C to remove the solvent to obtain a yellow oil material. The oily substance was distilled under reduced pressure to collect an effluent of 8 mmHg at 118-122 DEG C to obtain 11.31 g of a colorless transparent oil substance. The yield was 55.7% and the purity by GC inspection was 95.6065%.

_{^{1 HNMR (CDCl 3) δ (}} ppm): 7.15-6.77 (m, 5H), 4.45 (t, 2H), 3.79 (t, 2H)

Step 5 : (2S, 3R) -3- [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1- (2- phenoxyethyl) , 2, 2] octane

(4.55 mmol) of the (2S, 3R) stereoconstituent base was taken in a 50 ml eggplant type reaction flask and dissolved in 9 ml of chloroform to obtain a yellow transparent solution. 5.65 g (28.1 mmol ) And 25 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to the TLC test (TLC conditions: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2S, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (2- phenoxyethyl) -bromo-1-azabicyclo [ , 2, 2] octane was obtained. The yield was 79.12%.

The compound of Example 25 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through a half of Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

_{^{1 HNMR (D 2 O) δ}} (ppm): 7.18-6.76 (m, 10H), 5.86 (t, 2H), 4.39 (t, 2H), 3.98-3.71 (s, 2H), 3.47-3.18 (m, 7H), 1.92 (m, 1H), 1.81-1.66 (m, 5H), 1.59-1.36 (m, 8H).

[ Example  26] ( 2R, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Ethoxy ] -1- (2-phenoxyethyl) -bromo-l-azabicyclo [ 2] octane

Stage 1 : [ Example 1] Step 1 and same

2, Step 3 : [ Example 3]  2, Step 3 and same

Step 4 : [ Example 25] of 4  Step and same

Step 5 : (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (2- phenoxyethyl) , 2, 2] octane

1.435 g (4.55 mmol) of the (2R, 3R) stereoconstituent base was taken in a 50 ml eggplant type reaction flask and dissolved in 9 ml of chloroform to obtain a yellow transparent solution. 5.65 g (28.1 mmol ) And 25 ml of acetonitrile are added and stirred for 20-90 h at room temperature under nitrogen gas protection and proceed until complete reaction to the TLC test (TLC conditions: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxyethyl) -bromide- 1 -azabicyclo [ , 2, 2] octane was obtained. The yield was 76.56%.

The compound of Example 26 can be converted to the corresponding salt by reaction with other acids by removing the bromine atom through a half of the Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

_{^{1 HNMR (D 2 O) δ}} (ppm): 7.19-6.78 (m, 10H), 5.88 (t, 2H), 4.38 (t, 2H), 3.99-3.70 (s, 2H), 3.47-3.17 (m, 7H), 1.93 (m, 1H), 1.81-1.67 (m, 5H), 1.60-1.37 (m, 8H).

[ Example  27] ( 2R, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Ethoxy ]-One- Pe Bromo-ethyl-bromo-1-azabicyclo [2, 2, 2] octane

Stage 1 : [ Example 1] Step 1 and same

2, Step 3 : [ Example 3]  2, Step 3 and same

Step 4 : Preparation of methoxybenzene bromide

9.5 g (101 mmol) of phenol was put into a 150 ml three-necked flask, and 4.25 g (106 mmol) of sodium hydroxide was added thereto. A solution composed of 43.51 g (250 mmol) of 1,2-dibromomethane and 30 ml of anhydrous alcohol was added, By heating with an oil bath and proceeding with a refluxing reaction, a white solid precipitates. TLC checking is carried out until the phenol completes the basic phase reaction (TLC conditions: petroleum ether / ethyl acetate = 5.0 ml / 1.0 ml). After completion of the reaction, the solid was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure of the pump at 50 DEG C or lower to obtain a white solid oil substance. Petroleum ether was added to the residue, The solid is removed, and the filtrate is rotary evaporated under reduced pressure of the pump at 25-40 ° C to remove the solvent to obtain a yellow oil substance. The oily substance was distilled under reduced pressure to collect an effluent of 8 mmHg at 116-120 DEG C to obtain 10.75 g of a colorless transparent oil substance. The yield was 56.9%, and the purity by GC inspection was 95.6065%.

_{^{1 HNMR (CDCl 3) δ (}} ppm): 7.16-6.76 (m, 5H), 5.95 (s, 2H)

Step 4 : (2R, 3R) -3 - [(2-Cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1-phenoxymethyl-bromo-1-azabicyclo [ ]octane

2.871 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was placed in a 100 ml eggplant type reaction flask and 18 ml of chloroform was added to dissolve the solution to obtain a yellow transparent solution. Then, 10.29 g (55 mmol) of methoxybenzene bromide, 25 ml of nitrile is added and the mixture is stirred at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5 ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-phenoxyethyl-bromide-1-azabicyclo [ ] Octane was obtained, and the yield was 80.2%.

The compound of Example 27 can be converted to the corresponding salt by reaction with other acid by removing the bromine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

_{^{1 HNMR (D 2 O) δ}} (ppm): 7.21-6.76 (m, 10H), 5.89 (s, 2H), 3.97-3.73 (s, 2H), 3.48-3.18 (m, 7H), 1.95 (m, 1H), 1.80-1.58 (m, 5H), 1.61-1.38 (m, 8H).

[ Example  28] ( 2R, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2-phenyl) Ethoxy ]-One- Pe 1-azabicyclo [2, 2, < RTI ID = 0.0 > 2] octane

Stage 1 : [ Example 1] Step 1 and same

2, Step 3 : [ Example 3]  2, Step 3 and same

Step 4 : Preparation of phenylchloromethoxymethyl ether

9.5 g (101 mmol) of phenol was put into a 150 ml three-necked flask, and 4.25 g (106 mmol) of sodium hydroxide was added thereto. A solution composed of 28.75 g (250 mmol) of 1,3-dichloromethyl ether and 30 ml of anhydrous alcohol was added, And a reflux reaction is carried out, whereby a white solid is precipitated. TLC checking is carried out until the phenol completes the basic phase reaction (TLC conditions: petroleum ether / ethyl acetate = 5.0 ml / 1.0 ml). After completion of the reaction, the solid was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure of the pump at 50 DEG C or lower to obtain a white solid oil substance. Petroleum ether was added to the residue, The solid is removed, and the filtrate is rotary evaporated under reduced pressure of the pump at 25-40 ° C to remove the solvent to obtain a yellow oil substance. The oily substance was distilled under reduced pressure to collect an effluent of 8 mmHg at 106-119 DEG C to obtain 8.38 g of a colorless transparent oil substance. The yield was 48.1%, and the purity by GC inspection was 97.62%.

_{^{1 HNMR (CDCl 3) δ (}} ppm): 7.19-6.79 (m, 5H), 6.01 (s, 2H), 5.47 (s, 2H)

Step 5 : (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-phenoxymethoxymethyl-chloro- , 2] octane

2.871 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was placed in a 100 ml eggplant type reaction flask, and 18 ml of chloroform was added to dissolve the reaction mixture to obtain a yellow transparent solution. 9.49 g (55 mmol) of phenylchloromethoxymethyl ether (TLC condition: chloroform / methanol / ammonia = 5.0 ml / min) and 25 ml of acetonitrile, and the mixture was stirred at room temperature for 20 to 90 hours under nitrogen gas protection. 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-phenoxymethoxymethyl-chloro- 1-azabicyclo [ , 2] octane was obtained. The yield was 69.2%.

The compound of Example 28 can be converted to the corresponding salt by reacting with other acid by removing chlorine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

_{^{1 HNMR (D 2 O) δ}} (ppm): 7.19-6.77 (m, 10H), 6.02 (s, 2H), 5.32 (s, 2H), 3.98-3.68 (s, 2H), 3.49-3.19 (m, 7H), 1.96 (m, 1H), 1.82-1.57 (m, 5H), 1.60-1.36 (m, 8H).

[ Example  29] ( 2R, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2- Naphthyl ) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Step 1 : 230 g of 1-naphthyl-1-cyclophenylethylene oxide is obtained according to the method of Reference ^{( 2)} .

Step 2 : Alkali preparation of 3 - [(2-cyclopentyl-2-hydroxy-2-naphthyl) ethoxy] -1-azabicyclo [2,2,2] octane as R-3- quinuclidinol

18.72 g (147 mmol) of commercially available R-3-quinuclidinol was added, 190 ml of DMSO solution was added, and 7.59 g (190 mmol) of sodium hydride was added. The mixture was reacted at 20-60 ° C for 0.5 to 12 hours, , Adding a solution composed of 45.15 g (190 mmol) of 1-naphthyl-1-cyclopentylethylene oxide (manufactured by itself) and 45 ml of DMSO and heating to 20-70 ° C with an oil bath for 0.5-12 hours , 120 ml of ice water is added under an ice bath condition, and the inside is titrated while keeping the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated overnight to remove the drying agent by filtration and the solvent was removed under reduced pressure to give a red oil substance 3 - [(2-cyclopentyl-2-hydroxy-2-naphthyl) ethoxy] - 1-azabicyclo [2, 2, 2] octane free alkali was obtained, and the yield was 96.38%. This can be achieved by reacting (2R, 3R), (2S, 3R) -3 - [(2-cyclopentyl- 2- hydroxy- 2- naphthyl) ethoxy] -1- azabicyclo [ Alkaline.

Step 3 : Purification of 3 - [(2-cyclopentyl-2-hydroxy-2-naphthyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography and related purification

The sample of the second step is separated in a silica column, the methanol is added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample is monitored with a TLC plate, and the sample (2R, 3R ), And (2S, 3R), two stereoselectively arranged 3 - [(2-cyclopentyl-2-hydroxy-2-naphthyl) ethoxy] -1- azabicyclo [ (2R, 3R) stereochemistry can be purified by two free alkalis (2R, 3R) and (2S, 3R) according to the sequential order of elution and 3 - [(2-cyclopentyl- (2S, 3R) stereoselected 3 - [(2-cyclopentyl-naphth) ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained in a yield of 86.5% 2-hydroxy-2-naphthyl) ethoxy] -1-azabicyclo [2.2.2] octane free alkali was obtained, yielding 77.55%.

Step 4 : [ Example 1] Step 4 and same

Step 5 : (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-naphthyl) ethoxy] -1- (3- phenoxypropyl) 2, 2, 2] octane

3.322 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.033 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-naphthyl) ethoxy] -1- (3- phenoxypropyl) 2,2,2] octane was obtained. The yield was 80.3%.

The compound of Example 29 can be converted to the corresponding salt by reaction with other acid by removing chlorine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O) (ppm):? 7.21-6.66 (m, 12H),? 4.17-3.65 (m, 5H),? 3.444-3.13 2H), 2.00 (m, 1H), 1.84-1.42 (m, 13H).

[ Example  30] ( 2R, 3R ) -3 - [(2- Cyclopentyl Hydroxy-2-O- Chlorophenyl ) Et Yl] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Step 1: Preparation of 1-chloro-phenyl-1-O- cycloalkyl peltil ethylene oxide

1-O-chlorophenyl-1-cyclopentyl ethylene oxide is obtained by reacting O-phenyl-cyclopentyl ketone commercially available as a raw material according to literature ^{( 1)} .

  Acetonitrile (1880 ml) is taken in a 3 L three-necked flask. When dimethylsulfide and dimethylsulfuric acid are added, the mixture is slightly cooled and stirred for 1.5 hours at room temperature. When NaH (60%) is taken with stirring, it is added to the reaction solution several times to generate gaseous matter (in the case of an external cooler and anhydrous calcium chloride drying vessel), the mixture is added in the range of 30-40 min, And 355 g of O-chlorophenyl-cyclopentyl ketone. The reaction mixture was stirred for about 20 minutes at room temperature, heated to 40-45 ° C in an oil bath, allowed to react for 90 minutes, allowed to cool at room temperature I spend the night. After transferring the reaction mixture to a branch reaction flask, the solvent was removed with a water pump (40-42 ° C, -0.095 MPa), the remaining solid was ice-cooled to 0-5 ° C, and 2630 ml of ice water The reaction mixture was extracted with isopropyl ether (650 ml × 3 times), the ether layer was combined, washed with water until the solution became neutral (pH of the aqueous solution was 7.0) The ether layer is dried over anhydrous sodium sulfate and spent the night. The desiccant was filtered, and the solvent was removed under reduced pressure (40-42 DEG C, -0.095 MPa) and 315.8 grams of 119-132 DEG C / 3 mmHg effluent was obtained again with oil pump vacuum, yielding 83.36% .

¹ HNMR (CDCl ₃ )? (Ppm): 7.19-7.07 (m, 4H), 2.92-2.64 (m, 1H), 2.21 (s, 2H), 1.61-1.37 (m, 8H).

Step 2 : Preparation of 3 - [(2-cyclopentyl-2-hydroxy-2-O-chlorophenyl) ethoxy] -1-azabicyclo [ Alkali production

18.72 g (147 mmol) of commercially available R-3-quinuclidinol was added, 190 ml of DMSO solution was added, and 7.59 g (190 mmol) of sodium hydride was added. The mixture was reacted at 20-60 ° C for 0.5 to 12 hours, , A solution composed of 42.317 g (190 mmol) of 1-O-chlorophenyl-1-cyclopentylethylene oxide (manufactured by itself) and 45 ml of DMSO was added and heated to 20-70 ° C with an oil bath, The mixture is reacted for 12 hours, and 120 ml of ice water is added under an ice bath condition, and the internal temperature is maintained at 30 ° C or lower while being titrated. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated overnight to remove the drying agent by filtration and the solvent was removed under reduced pressure to give 3 - [(2-cyclopentyl-2-hydroxy-2-O-chlorophenyl) Ethoxy] -1-azabicyclo [2, 2, 2] octane free alkali was obtained. The yield was 96.31%. 2-oxabicyclo [2.2.2] hept-2-ene-3-yl) Octane glass alkali.

Step 3 : Preparation of 3 - [(2-cyclopentyl-2-hydroxy-2-O-chlorophenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography and related tablets process

The sample of step 1 was separated in a silica gel column, the methanol was added to the ammoniated dichloromethane or trichloromethane to form a fluid phase, the purity of the sample was monitored with a TLC plate, and the sample (2R, 2R, 2R, 3R), (2S, 3R) 3 - [(2-cyclopentyl-2- hydroxy-2- O- chlorophenyl) ethoxy] The octane free alkali can be purified by two free alkalis (2R, 3R) and (2S, 3R) according to the sequential order of elution, and (2R, 3R) -3 - [(2-cyclopentyl- (2S, 3R) -3 - [(2-fluorophenyl) ethoxy] -1-azabicyclo [ -Cyclopentyl-2-hydroxy-2-O-chlorophenyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained. The yield was 85.485%.

Step 4 : Same as step 4 of [Example 1]

Step 5 : (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- O- chlorophenyl) ethoxy] -1- (3- phenoxypropyl) Cyclo [2, 2, 2] octane

3.18 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and 18 ml of chloroform was added to dissolve to obtain a yellow transparent solution. 11.033 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- O- chlorophenyl) ethoxy] -1- (3- phenoxypropyl) Cyclopentadienyl] cyclo [2,3,2] octane was obtained. The yield was 82.73%.

The compound of Example 30 can be converted to the corresponding salt by reaction with other acid by removing chlorine atoms through the half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

^{1 HNMR (D2O) (ppm)} : δ7.33-6.65 (m, 9H), δ4.16-3.63 (m, 5H), δ3.45-3.12 (m, 8H), δ2.13 (m, 2H) , 2.02 (m, 1H), [delta] 1.83-1.43 (m, 13H).

[ Example  31] ( 2R, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2- (3- Pyridyl )) Et Yl] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Step 1 : Preparation of 3-pyridyl-cyclophenylketone

102.06 grams of magnesium powder was put into a 5 L three-necked flask, and a spherical cooling tube, anhydrous calcium chloride drying tube and thermometer were connected to the outside, and 1600 ml of THF and 1.06 g of iodine were added and stirred. 78.28 grams of cyclopentane bromide was taken, . After about 5 minutes from the initiation of the reaction, the reaction solution gradually changes from pale brown to colorless, and the internal temperature is raised to 63-65 ° C by itself. Separately, 547.93 grams of cyclopentane bromide is titrated, leaving it at about 35 min, and its reflux temperature is gradually raised to 75-77 ° C. The reflux reaction is carried out in the oil bath for 2 hours.

412.74 grams of 3-cyanopyridine pyridyl carbonitrile is added, diluted with 1600 ml of THF, titrated with the reaction solution, and refluxed for 4 hours in an oil bath. The internal temperature was lowered to 5-10 ° C., and 96 ml of ice water was titrated. After stirring for 20 min, the pH was adjusted to 2.0 by titrating with HCl. The mixture was heated under reflux for 3 hours, The organic layer was washed successively with 1% Na ₂ CO ₃ (500 × 3 times) and water (500 × 3 times), and the organic layer was washed with anhydrous magnesium sulfate (42 ° C, -0.095 MPa) and then distilled under reduced pressure using an oil pump to collect 332.26 grams of 6-7 mm Hg oil matter at 122-130 ° C.

_{^{1 HNMR (CDCl 3) δ (}} ppm): 9.31-7.70 (m, 4H), 2.36 (m, 1H), 1.63-1.47 (m, 8H).

Step 2 : Preparation of 1- (3-pyridyl) -1-cyclopentylethylene oxide

(3-pyridyl) -1-cyclopentylethylene oxide is obtained by reacting 3-pyridylphenyl-cyclophenylketone according to literature (1) as a raw material.

Acetonitrile (1880 ml) is taken in a 3 L three-necked flask. When dimethylsulfide and dimethylsulfuric acid are added, the mixture is slightly cooled and stirred for 1.5 hours at room temperature. When NaH (60%) is taken with stirring, it is added to the reaction solution several times to generate gaseous matter (in the case of an external cooler and anhydrous calcium chloride drying vessel), the mixture is added in the range of 30-40 min, , And 300 g of 3-pyridylcyclopentyl ketone. The reaction mixture was stirred for about 20 minutes at room temperature. The reaction mixture was heated to 40-45 ° C with an oil bath for 90 minutes, cooled to room temperature . After transferring the reaction mixture to a branch reaction flask, the solvent was removed with a water pump (40-42 ° C, -0.095 MPa), the remaining solid was ice-cooled to 0-5 ° C, and 2630 ml of ice water The reaction mixture was extracted with isopropyl ether (650 ml × 3 times), the ether layer was combined, washed with water until the solution became neutral (pH of the aqueous solution was 7.0) The ether layer is dried over anhydrous sodium sulfate and spent the night. The desiccant is filtered and the water pump is depressurized ((40-42 DEG C, -0.095 MPa) to remove the solvent, and then 285.5 grams of 121-131 DEG C / 3 mmHg effluent is obtained again with oil pump depressurization.

_{^{1 HNMR (CDCl 3) δ (}} ppm): 8.68-7.50 (m, 4H), 2.91-2.66 (m, 2H), 2.23-1.29 (m, 9H).

Step 3 : Preparation of 3 - [(2-cyclopentyl-2-hydroxy-2- (3- pyridyl)) ethoxy] -1- azabicyclo [ Octane glass alkali production

18.72 g (147 mmol) of commercially available R-3-quinuclidinol was added, 190 ml of DMSO solution was added, and 7.59 g (190 mmol) of sodium hydride was added. The mixture was reacted at 20-60 ° C for 0.5 to 12 hours, , A solution composed of 35.91 g (190 mmol) of 1- (3-pyridyl) -1-cyclopentylethylene oxide (prepared in-house) and 45 ml of DMSO was added and the mixture was heated to 20-70 ° C The reaction is carried out for 0.5 to 12 hours, 120 ml of ice water is added under an ice bath condition, and the inside is titrated while maintaining the internal temperature at 30 캜 or lower. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove the drying agent. The solvent was removed to obtain a red oil substance 3 - [(2-cyclopentyl-2-hydroxy- ) Ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained in a yield of 98.3%. 2-hydroxy-2- (3-pyridyl)) ethoxy] -1-azabicyclo [2, 2] octane glass alkali.

Step 4 : Purification of 3 - [(2-cyclopentyl-2-hydroxy-2- (3- pyridyl)) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography and Related refining process

The sample of step 3 was separated in a silica column, added to ammonia dichloromethane or trichloromethane to form a liquid phase, and the purity of the sample was monitored with a TLC plate. Under the present elution system, samples (2R, 3R ), And (2S, 3R) of the two stereoisomers of 3 - [(2-cyclopentyl-2-hydroxy-2- (3- pyridyl)) ethoxy] ] Octane free alkali can be purified by two free alkalis (2R, 3R) and (2S, 3R) according to the sequential order of elution and (2R, 3R) -3- [ (2S, 3R) stereoconfiguration 3 (yield: 85.5%) was obtained in the same manner as in Example 1, except that 19.52 g of alkali - [(2-cyclopentyl-2-hydroxy-2- (3-pyridyl)) ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained, 83.47%.

Step 5 : Same as step 4 of [Example 1]

Step 6 : (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- (3 pyridyl)) ethoxy] -1- (3- phenoxypropyl) Bicyclo [2, 2, 2] octane

3.18 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and 18 ml of chloroform was added to dissolve to obtain a yellow transparent solution. 11.033 g (51.3 mmol ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, 1- (3-phenoxypropyl) -bromo-l- (3-pyridyl) And 3.95 g of azabicyclo [2, 2, 2] octane were obtained. The yield was 81.7%.

The compound of Example 31 can be converted to the corresponding salt by reaction with other acids by removing chlorine atoms through the half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O) (ppm):? 8.72-6.63 (m, 9H),? 4.13-3.61 (m, 5H),? 3.44-3.13 (m, 8H) 2H), 2.01 (m, 1H), 1.82-1.45 (m, 13H).

[ Example  32] ( 2R, 3R ) -3 - [(2- Cyclopentyl -2-hydroxy-2- (2- Furyl )) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

Step 1 : Preparation of 2-furyl-cyclopentyl ketone

101.5 grams of magnesium powder was put into a 5 L three-necked flask, and a spherical cooling tube, anhydrous calcium chloride drying tube and thermometer were connected to the outside, and 1600 ml of THF and 1.05 g of iodine were added and stirred. 78.28 grams of cyclopentane bromide was taken, . After about 5 minutes after the reaction is completely initiated, the reaction liquid gradually changes from pale brown to colorless, and the internal temperature is raised to 62-65 ° C by itself. Separately, 548 grams of cyclopentane bromide is titrated, leaving it at about 35 min and its reflux temperature is gradually raised to 75-77 ° C. The reflux reaction is carried out in the oil bath for 2 hours.

404 grams of 2-furylcarbonitrile was added and 1600 ml of THF was added to dilute the solution. The solution was titrated to the reaction solution, and a reflux reaction was carried out in an oil bath for 4 hours. The internal temperature was lowered to 5-10 ° C., and 96 ml of ice water was titrated. After stirring for 20 min, the pH was adjusted to 2.0 by titrating with HCl. The mixture was heated under reflux for 3 hours, The organic layer was washed successively with 1% Na ₂ CO ₃ (500 × 3 times) and water (500 × 3 times), and the organic layer was washed with anhydrous magnesium sulfate (42 ° C, -0.095 MPa) and then distilled under reduced pressure using an oil pump to collect 272.6 grams of 6-7 mm Hg oil matter at 108-119 ° C.

_{^{1 HNMR (CDCl 3) δ (}} ppm): 7.39-6.70 (m, 3H), 2.36 (m, 1H), 1.65-1.45 (m, 8H).

Step 2 : Preparation of 1- (2-furyl) -1-cyclopentylethylene oxide

(2-furyl) -1-cyclopentyl ethylene oxide is obtained by reacting 2-furyl-cyclopentyl ketone as a starting material according to literature (1).

1780 ml of acetonitrile is put into a 3-liter three-necked flask. When dimethyl sulfide and dimethylsulfuric acid are added, the mixture is slightly cooled and stirred for 1.5 hours at room temperature. When NaH (60%) is taken with stirring, it is added to the reaction solution several times to generate gaseous matter (in the case of an external cooler and anhydrous calcium chloride drying vessel), the mixture is added in the range of 30-40 min, And 250 g of 3-pyridylcyclopentyl ketone. After stirring for about 20 minutes at room temperature, the mixture was heated to 40-45 ° C by heating in an oil bath for 90 minutes, cooled to room temperature . After transferring the reaction mixture to a branch reaction flask, the solvent was removed with a water pump (40-42 ° C, -0.095 MPa), the remaining solid was ice-cooled to 0-5 ° C, and 2630 ml of ice water The reaction mixture was extracted with isopropyl ether (650 ml × 3 times), the ether layer was combined, washed with water until the solution became neutral (pH of the aqueous solution was 7.0) The ether layer is dried over anhydrous sodium sulfate and spent the night. The desiccant is filtered and the solvent is removed from the water pump under reduced pressure (40-42 占 폚, -0.095 MPa), and then 231.6 grams of 111-121 占 폚 / 3 mmHg effluent is obtained again with oil pump decompression.

¹ HNMR (CDCl ₃ )? (Ppm): 7.35-6.50 (m, 3H), 2.93-2.65 (m, 2H), 2.26-1.27 (m, 9H).

Step 3 : Preparation of R-3-quinuclidinol 3 - [(2-cyclopentyl-2-hydroxy-2- (2-furyl)) ethoxy] Free alkali production

18.72 g (147 mmol) of commercially available R-3-quinuclidinol was added, 190 ml of DMSO solution was added, and 7.59 g (190 mmol) of sodium hydride was added. The mixture was reacted at 20-60 ° C for 0.5 to 12 hours, , And a solution composed of 33.88 g (190 mmol) of 1- (2-furyl) -1-cyclopentylethylene oxide (manufactured by itself) and 45 ml of DMSO was added and heated to 20-70 ° C -12 hours, 120 ml of ice water is added under an ice bath condition, and the internal temperature is maintained at 30 DEG C or lower while being titrated. 100 ml × 3 times with isopropyl ether, and the combined ether layer is washed with 100 ml * 3 times with saturated aqueous NaCl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated overnight to remove the drying agent by filtration and reduced pressure to remove the solvent to give a red oil substance 3 - [(2-cyclopentyl-2-hydroxy-2- Ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained in a yield of 95.32%. This can be achieved by reacting (2R, 3R), (2S, 3R) -3 - [(2-cyclopentyl- ] Octane glass alkali.

Step 4 : Purification and purification of 3 - [(2-cyclopentyl-2-hydroxy-2- (2-furyl) ethoxy] -1-azabicyclo [2,2,2] octane free alkali column chromatography Refining process

The sample of step 3 was separated in a silica column, added to ammonia dichloromethane or trichloromethane to form a liquid phase, and the purity of the sample was monitored with a TLC plate. Under the present elution system, samples (2R, 3R ), And (2S, 3R), two stereoisomers of 3 - [(2-cyclopentyl-2- hydroxy- 2- The octane free alkali can be purified by two free alkalis (2R, 3R) and (2S, 3R) according to the sequential order of elution, and (2R, 3R) -3 - [(2-cyclopentyl- (2S, 3R) stereoselective 3- [2- (2-furyl)) ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained in a yield of 83.5% 18.03 g of (2-cyclopentyl-2-hydroxy-2- (2-furyl)) ethoxy] -1-azabicyclo [2,2,2] octane free alkali was obtained, yielding 84.37% .

Step 5 : Same as Step 3 of [Example 1]

Step 6 : (2R, 3R) -3 - [(2-Cyclopentyl-2-hydroxy- 2- (2- furyl) ethoxy] -1- (3- phenoxypropyl) Cyclo [2, 2, 2] octane

2.78 g (9.1 mmol) of the (2R, 3R) stereoconstituent base was taken in a 100 ml eggplant type reaction flask and dissolved in 18 ml of chloroform to obtain a yellow transparent solution. 11.033 g (51.3 mmol) of 3-bromopropoxybenzene ) And 50 ml of acetonitrile are added, and the reaction is carried out at room temperature for 20-90 hours under the protection of nitrogen gas until the reaction is complete by TLC (TLC condition: chloroform / methanol / ammonia = 5.0 ml / 1.5ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, (2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- (2- furyl)) ethoxy] -1- (3- phenoxypropyl) And 3.97 g of bicyclo [2, 2, 2] octane was obtained. The yield was 83.9%.

The compound of Example 32 can be converted to the corresponding salt by reaction with other acids by removing the chlorine atom through the half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O) (ppm):? 7.32-6.19 (m, 8H),? 4.14-3.60 (m, 5H),? 3.42-3.11 2H), 1.97 (m, 1H),? 1.83-1.46 (m, 13H).

[ Example  33] ( 2R, 3R ) 3 - [(2- Cyclopentyl -2-hydroxy-2- ( 3 pyridyl )) Ethoxy ] -1- (3-phenoxypropyl) -bromo-l-azabicyclo [ 2] octane

1, 2, 3, and 4 steps : [Example 31] Same as steps 1, 2, 3, and 4.

Step 5 : Same as step 4 of [Example 1]

Step 6 : Same as Step 6 of [Example 31]

Step 7 : (2R, 3R) -3 - [(2-Cyclopentyl-2-methoxy- 2- (3pyridyl) ethoxy] -1- (3- phenoxypropyl) Cyclo [2,3,2] octane

(2R, 3R) -3 - [(2-cyclopentyl-2-methoxy-2- (3- pyridyl)) ethoxy] -1- (3- phenoxypropyl) (2.87 g, 4.87 mmol) of [2, 2, 2] octane was placed in a 100 ml eggplant type reaction flask, and 30 ml of acetonitrile was added to dissolve the solution. Then, 0.5 g of NaH was added and 10 ml of a bromomethane acetonitrile solution (TLC condition: chloroform / methanol / Ammonia number = 5.0 ml / 1.5), and the mixture was stirred for 20-90 h at room temperature under nitrogen gas protection. ml / 2d). After the completion of the reaction, the reaction mixture was rotary evaporated under reduced pressure at 25-40 DEG C to remove the solvent to obtain a yellow oil substance. Ethyl ether was added to precipitate a large amount of solid, Ethoxy] -1- (3-phenoxypropyl) -bromo-l- (3-pyridyl) 2.19 g of azabicyclo [2, 2, 2] octane was obtained, and the yield was 80.37%.

The compound of Example 33 can be converted to the corresponding salt by reaction with other acid by removing chlorine atom through a half of the compound with Ag ₂ O to form a hydroxide. Examples of the salt formed by a pharmaceutically acceptable acid include Include salts derived from inorganic acids, inorganic acid salts such as hydrochloride, bromide, iodide, nitrate, carbonate, bicarbonate, phosphate, hydrogen phosphate, phosphate dihydrogen phosphate, sulfate, bisulfate and phosphite, In the salts derived from non-toxic organic acids, the organic acids may be, for example, acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, para- , Tartaric acid, methanesulfonic acid, glucuronic acid or galactonic acid. And salts of amino acids such as arginine.

¹ H NMR (D ₂ O) (ppm): δ 8.77-6.66 (m, 9H), δ4.15-3.65 (m, 5H), δ3.44-3.13 (m, 11H), δ2.16 2H), 2.03 (m, 1H),? 1.85-1.43 (m, 13H).

Experimental Example  One: Carbacoal (CCh) on  Of guinea pig bronchial smooth muscle contraction induced by Example  The antagonistic strength of the compound

1. Method:

Guinea pig ex vivo bronchial smooth muscle specimen preparation: After anesthetized guinea pigs with urethane, Krebs-Henseleit (KH) to quickly pass a 5% CO ₂ and 95% O ₂ gas mixture taking the bronchus between the larynx and the keel solution (composition (g / L): NaCl 6.92, KCl 0.35, CaCl ₂ 0.28, KH ₂ PO ₄ 0.16, MgSO ₄ .7H ₂ O 0.4568, NaHCO ₃ 2.1, glucose 2.0). After separating the connective tissue and fat around the bronchus, the bronchial flap was separated by a surgical scissor with a width of about 3 mm and a length of 20 mm. Both ends of the bronchial flap were fixed with 4 ~ Put in a constant-temperature bath (pH 7.4) and continuously pass a mixed gas containing 5% CO ₂ and 95% O ₂ . Connect the muscle tension transducer to the top and record the change in muscle tension after 1.0 g of stable tension on the specimen. Replace the nutrient once every 20 min and equilibrate for 60 min before proceeding.

Drug administration method: 3 × 10 ^-6 mol / LCCh is added to the bath after stabilization of the bronchial stump, and the cumulative dose of 10 ^-9 to 10 ^-5 mol, respectively, after the bronchial contraction tension reaches the peak, is administered in the Magnus bath by the drug administration method After the addition of the example compound, ipratropium bromide and thiotropium bromide, the relaxation status of the bronchial strips is observed, and if the reaction does not occur (subthreshold concentration) Appears, the next dose is added after the strain reaches the relaxation equilibrium. The operation is repeated until the contraction curve reaches a minimum value. Finally, 10 ^-6 mol / L isoprenaline is added to allow the peak to relax and record the curve.

Statistical methods: Results are expressed as means ± standard deviation, and statistics are run with Sigma Stat statistical software. Data are analyzed with variance and comparisons between averages of multiple samples are carried out by the Student-Newman-Keuls (SNK) test with a statistical test level α = 0.05 (double measurement). The EC ₅₀ (95% confidence limit) is calculated using software from POMS version 2.0 of the Shanghai Science and Technology Publishing Co.

2, conclusion:

3 × 10 ^-6 mol / L CCh causes a sustained and stable contraction reaction in the bronchial smooth muscle of the guinea pig. In the cumulative dose drug administration method, the compound of Example and the comparative drugs ipratropium bromide and thiotropium bromide were added to a Magnus bath, and each of the compound of Example and the comparative drug relaxed CCh-induced bronchial smooth muscle contraction The results are as shown in Table 2.

3. Results

[Table 2] concentration of 3 × 10 ^-6 mol / L in the compounds of the invention for the guinea pig bronchial smooth muscle contraction induced by CCh vitro antagonism IC ₅₀ (μM)

As can be seen from the results in Table 2, the compounds of the respective Examples had a remarkable blocking action against M, among which the action of the (2R, 3R) type compound was strongest, and the compounds and the positive control The working intensity of rofium bromide and thiotropium bromide is similar. The onset time of the effect of the compound of the present invention and ipratropium bromide is faster than that of thiotropium bromide, and the effect of thiotropium bromide is slower on the contrary. The duration of action of the compounds of the present invention and thiotropium bromide is long.

Experimental Example 2: M  The binding and selectivity of the compounds of the present invention to three subtypes of receptors

1. Methods: The already transfected Chinese hamster ovary cells (CHO) m ₁ , m ₂ , and m ₃ cells were cultured in DMEM medium (15% fetal bovine serum, L-glutamine, 1% / ≪ / RTI > antifungal) in an incubator at 37 < 0 > C and 5% CO ₂ . The cells in the culture bottle were grown and proliferated to form monolayer cells. When the bottom of the bottle was covered with about 90% of the cells, the medium was discarded and the cells were washed twice with PBS (pH 7.4) buffer solution and then washed with cold phosphate buffer solution (pH7.7, scrape the cells comprising LMgCl _2). The collected cells are homogenized with a Teflon glass homogenizer, the homogenization solution is centrifuged at 20000 rx 20 min at a low temperature, and the precipitate is homogenized with a membrane protein suspension by adding a reaction buffer solution (pH7.7, including 5 mmol / L MgCl ₂ ). The amount of protein added to each reaction tube is m ₁ (about 0.05 mg), m ₂ (0.05 mg) and m ₃ (0.1 mg), the specificity of [ ³ H] -QNB is 0.1-2.16 nmol / L, The reaction was stopped at 25 ° C. for 30 minutes, and the reaction was stopped with a cold reaction buffer, and then collected in a glass fiber filtration membrane with a multi-head cell collector. , The filtration membrane is put into a liquid scintillation bottle, 5 ml of liquid scintillation liquid is added, and the cpm is measured with a liquid scintillation counter while avoiding light. The Bmax and Kd values are calculated by graphicpad prism software. To the M receptor The final concentration of ³ H-QNB each tube bar, the addition of culture medium to the title that has no selectivity than is _{m 1, m 3 (1.042nmol /} L), m 2 (1.81nmol / L) as well as different concentrations of Addition of the unidentified agonist Pirenzepine (PZ, m ₁ selective agonist) or gallamine (GI, m ₂ selective agonist) or 4-DAMP (m ₃ selective agonist) ^-10 to 10 ^-4 mol / L, all 11 of them are used, and the same amount of membrane protein sample is added, and the total reaction volume is 300 μ, and the competitive binding reaction is carried out. Separately, non-specific binding tubes are prepared, (At a final concentration of 1 μM, the non-specific binding is measured, the reaction is carried out at 25 ° C. for 30 min, the reaction is stopped with a cold reaction buffer solution and then collected on a glass fiber filtration membrane with a multi- After the filtration, Add 5 ml of liquid scintillation fluid to the light bottle and incubate overnight without light. Measure the cpm with a liquid scintillation counter. Calculate Ki values for each of the three M receptor subtypes of the agonist with graphpad prism software. Values, and compare the selectivity of PZ, gI, 4-DAMP with the M-acceptor subtype of the compound to be measured.

2. Results

[Table 3]

3. Conclusion

This experiment demonstrates the M-type subtype selectivity of the compounds of the present invention to CHO cells of transfected m ₁ , m ₂ , m ₃ three M receptor subtype cDNAs. The pharmacological properties of pirenzepine, gallamine, and 4-DAMP, and the competition inhibition of these and three cells, these cells could be used to test drug receptor selectivity. Experimental results showed that the inventive compounds of the present invention had the highest selectivity for the m ₃ receptor, the next for the m ₁ receptor, and the lowest selectivity for the m ₂ receptor, among which m ₃ and m ₁ receptors All have relatively strong action. Rhinitis, airway hyperreactivity, chronic bronchitis, COPD and gastrointestinal ulcers, have a significant advantage over the prior art.

Experimental Example  3: On methacholine (Mch)  Of guinea-pig bronchoconstriction induced by Example  Antagonism of compounds Strength Course  Measurement of duration of action

1. Method:

1 tidal volume, airway velocity, light pulse pressure measurement: Guinea pig is anesthetized by intraperitoneal injection of urethane at 1.5 g / kg. The guinea pigs were placed in the chef test smog box and inserted into the fourth to fifth ribs of the guinea pig breast through the needle of the chest tube insertion tube. The pressure in the thoracic cavity can be measured (note that the water column of the water pressure gauge is negative and also moves up and down with the respiration of the guinea pig). After stabilization, use the MedLab bio-signal acquisition system to measure hop rate, airway velocity, and light pulse pressure of guinea pigs before the administration of Mch, and record the baseline values. Intravenously inject Mch at a dose of 10 μg / kg. Observe changes in guinea pig airway velocity, tidal volume and cystic pressure within 5 min. Calculation of R _aw and C _dyn : After inhaling the Mch with aerosol, calculate the percent change of R _aw value and the percentage of C _dyn fall rate.

The calculation formulas for R _aw and C _dyn are as follows.

Capacity effect relationship: All 27 guinea pigs of each example compound were randomly divided into three groups, 15 guinea pigs were added to 1 占 퐂 / kg of Example compounds 4, 10, 14 and 26, and Example compounds 4 and 10 , 14, 26, and 10 μg / kg of the compounds of Examples 4, 10, 14, and 26. After the administration of the drug at the above concentration for 30 minutes, the Mch of 10 μg / kg body weight was intravenously injected, (R _aw ) and pulmonary dynamic adaptability (C _dyn ).

Time effect relationship: After anesthetizing the guinea pigs, 10 μg / kg and 5 μg / kg of Example compounds 4, 10, 14 and 26 are titrated with air. After the administration of the drug, Mch of 10 μg / kg body weight was injected intravenously after 0.25h, 0.5h, 1h, 1.5h, 2h, 4h, 6h, 12h and 24h, and the airway resistance ( R _aw ) ( C _dyn ) is measured.

2, result:

Dose effect relationships: Example Compound 4, 10, 14, the drug amount of 26 are each 1μg / kg, 3μg / kg and 10μg / kg, after appropriate administration airways 30min, to the Mch of 10μg / kg body weight intravenously percussion The airway resistance (R _aw ) and lung dynamic adaptability (C _dyn ) within 5 _min were measured. The results are shown in the following table.

[Table 4] Convolution-dose effect (Mean ± S.E.M.) relationships of Examples 4, 10, 14, and 26 for Mch-induced guinea pig tissue shrinkage response

Intravenous injection of Mch 10 μg / kg results in a 328% increase in airway resistance and a 73% decrease in lung dynamic adaptability of guinea pigs. Examples 4, 10, 14, and 26 When the compounds 1, 3, and 10 μg / kg are appropriately administered by the airway, the increase in the airway resistance and the decrease in the lung dynamic adaptability are suppressed by dose dependency. The inhibition rates of the three dose groups of the Example Compound 4 were 64.2% ( p <0.01 ), 86.1% ( p <0.001 ) and 90.8% ( p <0.001 ), respectively, and the inhibition rates on the lung dynamic adaptive descent were 11.2% ( p> 0.05 ), 46.6% ( p <0.001 ) and 50.0% ( p <0.001 ). The inhibitory rates of the three dose groups of the Example Compound 10 were 63.7% ( p <0.01 ), 84.5% ( p <0.001 ) and 91.3% ( p <0.001 ) 10.9% ( p> 0.05 ), 45.9% ( p <0.001 ) and 49.8% ( p <0.001 ). The inhibitory rates of the three dose groups of the compound of Example 14 were 63.5% ( p <0.01 ), 85.4% ( p <0.001 ) and 90.5% ( p <0.001 ), respectively, and the inhibition rates on the lung dynamic adaptive descent were 11.0% ( p> 0.05 ), 46.1% ( p <0.001 ) and 49.5% ( p <0.001 ). The inhibition rates of the three dose groups of the Example 26 compound were 64.4% ( p <0.01 ), 87.2% ( p <0.001 ) and 92.1% ( p <0.001 ), respectively, and the inhibition rates on the lung dynamic adaptive descent were 11.0% ( p> 0.05 ), 47.1% ( p <0.001 ) and 49.9% ( p <0.001 ).

Time effect relationship: Intravenous injection of Mch 10 μg / kg increases airway resistance of guinea pig by 328%. After 0.25 h of airway administration of 10 μg / kg of Example Compound 4, 10, 14, 26 to guinea pigs, the inhibition rate for airway resistance increase is above 80% and may reach a maximum inhibition rate of 90% or more after 1 h. As time elapsed, the inhibition rate for airway resistance elevation after 24 h was still above 85% and also showed statistical significance ( p < 0.01 to 0.001 ) when compared to the solvent control group. To confirm the accuracy of the results, according to the results of lowering the dose of the drug of Examples 4, 10, 14 and 26 to 5 μg / kg, guinea pigs were administered 5 μg / kg of Example Compound 4, 10, 14, After one 12 h, the airway resistance inhibition rate was 85% or more ( p <0.001 ) and the airway resistance suppression rate after 24 h was 65% or more ( p <0.01 ). Comparing 10 μg / kg and 5 μg / kg of Example Compound 4, 10, 14, 26 to guinea pigs after 12 hours of airway administration, there is no significant difference in airway resistance suppression. However, when comparing 10 μg / kg and 5 μg / kg of the compounds of Examples 4, 10, 14 and 26 after 24 hours, there was a significant difference in the airway resistance suppression rate ( p <0.05 ). As can be seen from the above results, 10 μg / kg and 5 μg / kg of Example Compound 4, 10, 14 and 26 exceeded 24 h in airway administration time, to be.

The present invention also provides a compound as shown in Table 5, and its antagonistic concentration is 3 x 10 &lt; RTI ID = 0.0 &gt; ^-6 mol / L CCh  Induced guinea pig bronchial smooth muscle contraction antagonism IC ₅₀ (μM) were measured.

[Table 5] Other compounds synthesized in the present invention The compounds of the present invention against guinea pig bronchial smooth muscle contraction induced by CCh with a nonlinearity and concentration of 3 × 10 ^-6 mol / L have an in vitro antagonistic IC ₅₀ (mM)

Experimental Example  5: Composition and its preparation

Preparation and methods of levizers, nasal sprays, aerosols, powder sprays, aerosol inhalants and tablets

1. Single Prescription Fee

Example Compound 16 3 mg

Benzalkonium chloride 3 mg

H ₂ O 10 ml

The active ingredient, Example Compound 10 and the antimicrobial agent (benzalkonium chloride) were dissolved in H ₂ O and injected into a small brown bottle, with a fusiform lid, have.

The single prescription detergent may be dissolved in 2.0 ml to 20 mg of water per 10 ml of water and may be formulated with different concentrations of detergent. The amount of antimicrobial benzalkonium chloride used may vary within the range of 1-5 mg.

A single prescription dispenser is 2-3 drops (0.1 ml-0.15 ml) / nasolabug per dose, approximately 20-300 μg / nonspecific dose.

2. Complex prescription medicine

Example Compound 10 2.5 mg

Phenotereol 10 mg

Benzalkonium chloride 5mg

H ₂ O 10 ml

(Example compound 10 and phenoterol) and an antimicrobial agent (benzalkonium chloride) were dissolved in H ₂ O, injected into a small brown bottle and further equipped with a fusiform cover, Can be used for titration. The amount of antimicrobial benzalkonium chloride can be varied within the range of 1-5 mg. The combined prescription medicines are 2-3 drops (0.1 ml-0.15 ml) / nasolabug per dose, about 25 / nasally administered dose.

3. Metering Pump Small Spray

Example Compound 4 3.33 mg

Benzalkonium chloride 5.00 mg

Add 1N HCl until pH 4-6

Pure H ₂ O 2.0 ml

Under the production conditions of 100,000 class, the above components are dissolved in pure H ₂ O, injected into a bottle, and a dosing pump suitable for nasal aerosol is installed. The pump has a pumping amount of 70-90 μl once. 1-2 pumping / non-pumping each time, about 21-60 μg / nonspecific dose.

The amount of Compound 4 can be increased to obtain more usage when treating a severe patient.

4. Quantitative aerosols with propellant

Component weight

Example Compound 4 10 mg

2.4 g of alcohol

Oleic acid 7.0 mg

HFA-134a 11.75 g

Example Compound 4 may be dissolved with alcohol and oleic acid, and then injected with HFA-134a one time. Then, under a production condition of 100,000 tons, the surfactant was mixed with the launching reagents 1-bromo-trichloromethane, 2-bromo-dichloromethane and 4-bromo-dichloroethane according to proportions and then charged into a pressure- And inject it. 10 g for each bottle, 100 mg for one pumping, and 20 μg of Example Compound 4.

5. Capsule powder spray

Capsule type powder spray consists of the following components.

Example Compound 4 0.05 g

Lactose 98.95g

Sodium benzoate 1.0 g

Example Compound 4, lactose, and sodium benzoate were finely pulverized to a particle diameter of 5 탆 or less under a production condition of 100,000-fold weight, and then sufficiently and uniformly stirred and sealed in capsules. Each capsule is 40 mg, and 20 μg of the compound of the present invention can be inhaled at one time. In the medicinal composition of the present example of the respiratory diseases, lactose is a diluent and the diluent is also arabinose, glucan, mannitol, Xylitol, sucrose, fructose, sorbitol, maltose, amino acid or glucose can be selected. Sodium benzoate is a lubricant, and magnesium stearate can also be used as a lubricant.

6. Refining

Example Compound 5 5 g

Lactose 71.5g

Microcrystalline cellulose 22 g

Magnesium stearate 1.5 g

Lactose and microcrystalline cellulose were uniformly mixed with Example Compound 6, magnesium stearate was added, uniformly mixed, and tacked with a drying method, and 100 mg was added per each egg.

7. Inhalation solution

Example Compound 10 100 mg

Physiological saline 1000ml

Example Compound 10 is dissolved in 800 m of physiological saline, transferred to a 1000 ml volumetric flask, physiological saline is supplemented to the scale, and then the solution is divided into ampoules, 1 ml / bottle, and heated at 115 캜 for 30 minutes.

Claims (12)

In formula I,
n is 1 to 7;
R ₁ is a C ₃ -C ₇ hydrocarbon group which may be unsubstituted or optionally substituted with halogen, alkoxy, alkoxy, hydrocarbon, heterocycle, or aryl groups, but is not limited thereto ;
R ₂ is an aryl group which may be unsubstituted or optionally substituted;
R ₃ is a hydroxy group, a halogen, an alkoxy group or an acyloxy group, and the alkoxy group or the acyloxy group may be unsubstituted and may optionally be substituted with a halogen, a hydroxy group, an alkoxy group, a hydrocarbon group, an alkoxy group, Lt; / RTI &gt;group;
R ₄ and R ₅ may or may not be present and may independently be selected from substituents such as halogen, a hydroxy group, an alkoxy group, a hydrocarbon group, an alkoxy group, a hydrocarbon group, a heterocycle, and an aryl group;
Y is a C ₁ -C ₇ linear or branched alkyl group or - (CH ₂ -O-CH ₂ ) _m- , m is 1-3, and this group may be optionally substituted;
X ^- is an acid group or a hydroxy group,
Compounds such as formula I, pharmaceutically acceptable salts, solvates, precursors and optical isomers thereof. The method according to claim 1,
n is 1 to 3, R &lt; ₁ &gt; is an unsubstituted cycloalkyl group;
R ₂ is a phenyl group, a heteroaryl group containing one or more hetero atoms, a naphthyl group or a biphenyl group, which may be unsubstituted or optionally substituted, the substituent may be one or more, Halogen, a hydroxy group, a phenyl group, -OR ₆ , -SR ₆ , -NR ₆ R ₇ , -NHCOR ₆ , -CONR ₆ R ₇ , -CN, -NO ₂ , -COOR ₆ , -CF ₃ or C ₁ -C A straight chain or branched chain hydrocarbon group of 1 to ₄ carbon atoms; R ₆ and R ₇ may be a hydrogen atom, a C ₁ -C ₄ linear or branched hydrocarbon group, or jointly form a cyclic hydrocarbon group;
R ₃ is a hydroxy group or a methoxy group;
Y is a methyl group, an ethyl group, a propyl group or - (CH2-O) ₂ -; &Lt; / RTI &gt; 3. The method according to claim 1 or 2,
n is 1;
R ₁ is a cyclopentyl group or a cyclohexyl group;
R ₂ is an unsubstituted phenyl group, a pyridyl group, a furyl group or a thienyl group;
Y is an ethyl group or a propyl group; &Lt; / RTI &gt; The method according to any one of the preceding claims,
X ^- is an acid or hydroxyl group of a pharmaceutically acceptable inorganic acid such that the Formula I compound is in the form of a pharmaceutically acceptable salt or quaternary ammonium salt group, and the formed pharmaceutically acceptable salt is a hydrochloride, bromide, iodine Wherein the compound is selected from the group consisting of salts, nitrates, carbonates, bicarbonates, phosphates, hydrogen phosphates, phosphates, sulphates, bisulfates and phosphites. 4. The method according to any one of claims 1 to 3,
X ^- is an acid of a pharmaceutically acceptable organic acid such that the compound of formula I is in the form of an organic acid salt and the organic acid is selected from the group consisting of acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, Phthalic acid, benzenesulfonic acid, paratoluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, glucuronic acid, galactonic acid or amino acid. The method of claim 1,
(2S, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2S, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2R, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2] octane;
(2S, 3R), (2R, 3S) -3- [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] Cyclo [2, 2, 2] octane;
(2R, 3R), (2S, 3S) -3 - [(2-cyclopentyl-2-hydroxy-2- phenyl) ethoxy] Cyclo [2, 2, 2] octane;
(2S, 3R) -3- [(2-cyclohexyl-2-hydroxy-2-phenyl) ethoxy] 2] octane;
(2S, 3S) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2R, 3R) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2R, 3S) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2] octane;
(2R, 3S), (2S, 3R) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] Cyclo [2, 2, 2] octane;
(2R, 3R), (2S, 3S) -3 - [(2-cyclohexyl-2-hydroxy-2- phenyl) ethoxy] Cyclo [2, 2, 2] octane;
(2S, 3R) -3 - [(2-cyclobutyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2S, 3S) -3- [(2-cyclobutyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2R, 3S) -3 - [(2-cyclobutyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2] octane;
(2R, 3R) -3 - [(2-cyclobutyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2] octane;
(2R, 3S), (2S, 3R) -3 - [(2-cyclobutyl- Cyclo [2, 2, 2] octane;
(2R, 3R), (2S, 3S) -3 - [(2-cyclobutyl-2-hydroxy-2- phenyl) ethoxy] Cyclo [2, 2, 2] octane;
(2S, 3R) -3 - [(2-cyclopropyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2R, 3S) -3 - [(2-cyclopropyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2S, 3S) -3 - [(2-cyclopropyl-2-hydroxy-2- phenyl) ethoxy] -1- (3- phenoxypropyl) 2] octane;
(2R, 3R) -3 - [(2-cyclopropyl-2-hydroxy-2- phenyl) ethoxy] 2] octane;
(2R, 3S), (2S, 3R) -3- [(2-cyclopropyl-2-hydroxy-2- phenyl) ethoxy] Cyclo [2, 2, 2] octane;
(2R, 3R), (2S, 3S) -3 - [(2-cyclopropyl-2-hydroxy-2- phenyl) ethoxy] Cyclo [2, 2, 2] octane;
(2S, 3R) -3- [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] 2] octane;
(2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] 2] octane;
(2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-phenoxymethyl-bromo-1-azabicyclo [2.2.2] octane;
(2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-phenyl) ethoxy] -1-phenoxymethoxymethyl-chloro- octane;
(2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2-naphthyl) ethoxy] -1- (3- phenoxypropyl) , 2] octane;
(2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- o- chlorophenyl) ethoxy] -1- (3- phenoxypropyl) , 2, 2] octane;
(2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- (3- pyridyl)) ethoxy] -1- (3- phenoxypropyl) [2, 2, 2] octane;
(2R, 3R) -3 - [(2-cyclopentyl-2-hydroxy-2- (2- furyl)) ethoxy] 2, 2, 2] octane;
(3-phenoxypropyl) -bromo-l-azabicyclo [2.2. &Lt; RTI ID = 0.0 & 2, 2, 2] octane; &Lt; / RTI &gt; A pharmaceutical composition comprising a compound of any one of claims 1 to 5 and a pharmaceutically acceptable carrier, wherein the composition can be in any suitable formulation and is preferably a formulation for inhalation drug administration, nasal drug administration; The composition may also include or exclude other drugs used in the administration of one or more of the combined drugs. A process for the preparation of the compound of claim 1.
(One)

(2)

(3)

(4) reacting intermediate 2 with intermediate 4 to obtain a compound of formula (I)
&Lt; / RTI &gt; 8. The method of claim 7,
Further comprising, after step (2), purifying and separating the chemical isomer of intermediate 2. 9. The method according to claim 7 or 8,
Wherein after the step (4), the compound is reacted with Ag ₂ O to remove the halogen to form a hydroxyl group, and can be converted to other acid groups by reacting with other acids. Use of a compound of any one of claims 1 to 5 in the manufacture of a medicament for treating a disease associated with the M receptor. 11. The method of claim 10,
The diseases are selected from the group consisting of rhinitis, rhinitis following cold, chronic bronchitis, airway hyperresponsiveness, asthma, chronic obstructive pulmonary disease, cough, urinary incontinence, urinary frequency, overactive bladder syndrome, bladder spasms, cystitis, irritable bowel syndrome, A gastrointestinal disorder such as gastric cancer.